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O'Keefe, Kaitlyn, Andrew Elliott, Chad Livasy, Meghan Steiner, Irene Kang, Dave S. B. Hoon, Wolfgang Michael Korn et al. "HER2 alterations and prognostic implications in all subtypes of breast cancer." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 1041. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.1041.
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1041 Background: Amplification or overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is present in about 15-20% of breast cancers & is a prognostic & predictive biomarker. Additional ERBB2/HER2 alterations have become apparent on tumor next generation sequencing (NGS), including activating kinase domain mutations & fusions. Methods: DNA NGS (592 gene panel or whole exome) data from 12,153 breast samples retrospectively reviewed for ERBB2 alterations with RNA whole-transcriptome sequencing (WTS) data available for 7289 (60%) samples. Gene fusions detected using the ArcherDx fusion assay or WTS. Clinicopathologic features were described including breast cancer subtype, age, & biopsy site. HER2 status determined according to 2018 ASCO-CAP guideline. Overall survival obtained from insurance claims & Kaplan-Meier estimates were calculated for defined patient (pt) cohorts. Statistical significance was determined using Chi-square & Wilcoxon rank sum tests. Results: ERBB2 mutations ( ERBB2mts) were identified in 3.2% (n = 388) of tumors overall & most common in liver metastases (113/1972, 5.7%). ERBB2mts were found more in breast lobular tumors compared to ductal tumors (10 vs 2.1%, p < 0.001). HER2+ tumors had higher frequency of ERBB2mts compared to HER2- (4.3 vs 3%, p = 0.028). Tumors with score of 0 by immunohistochemistry demonstrated lower rate of ERBB2mts (0+ 2.2%, 1+ 3.5%, 2+ 4.5%, 3+ 3.45%, p < 0.05). Among HER2- tumors, ERBB2mts were present in 3.6% of hormone receptor (HR)+/HER2- & 1.9% of TNBC. Metastatic tumors had a higher rate of ERBB2mts compared to locoregional breast tumors (3.8 vs 2%, p < 0.001), with increased rates of activating mutations S310F (0.1 vs 0.0%, p < 0.05) & D769H (0.3 vs 0.1%, p < 0.05), & the resistance mutation L755S (1.2 vs 0.6%, p < 0.01). Compared to ERBB2-WT, ERRB2mts were associated with decreased ERBB2 transcripts levels in HER2+ samples (222 vs 441 transcripts per million [TPM], p < 0.001) & increased levels in HER2- samples (73 vs 35 TPM, p < 0.001). High tumor mutational burden (≥ 10 mut/Mb) & ERBB3 mutations were more common in ERBB2mts compared to ERRB2-WT (16.7 vs 7.7%, p < 0.001; 10.6 vs 0.8%, p < 0.001). ERBB2 fusions were rare (0.49%) with 97% occurring in HER2+ tumors. Of 8358 pts with outcome data, prognosis (HR 1.2, P = 0.06) & response to chemotherapy (HR 1.1, P = 0.42) was similar between pts with HER2- ERBB2mt & ERBB2-WT. Conclusions: ERBB2mts & fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, & lobular histology tumors - & did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy & may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts & clinical outcomes from this approach are under investigation.
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O'Keefe, Kaitlyn, Andrew Elliott, Chad Livasy, Meghan Steiner, Irene Kang, Dave S. B. Hoon, Wolfgang Michael Korn et al. "HER2 alterations and prognostic implications in all subtypes of breast cancer." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 1041. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.1041.
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1041 Background: Amplification or overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is present in about 15-20% of breast cancers & is a prognostic & predictive biomarker. Additional ERBB2/HER2 alterations have become apparent on tumor next generation sequencing (NGS), including activating kinase domain mutations & fusions. Methods: DNA NGS (592 gene panel or whole exome) data from 12,153 breast samples retrospectively reviewed for ERBB2 alterations with RNA whole-transcriptome sequencing (WTS) data available for 7289 (60%) samples. Gene fusions detected using the ArcherDx fusion assay or WTS. Clinicopathologic features were described including breast cancer subtype, age, & biopsy site. HER2 status determined according to 2018 ASCO-CAP guideline. Overall survival obtained from insurance claims & Kaplan-Meier estimates were calculated for defined patient (pt) cohorts. Statistical significance was determined using Chi-square & Wilcoxon rank sum tests. Results: ERBB2 mutations ( ERBB2mts) were identified in 3.2% (n = 388) of tumors overall & most common in liver metastases (113/1972, 5.7%). ERBB2mts were found more in breast lobular tumors compared to ductal tumors (10 vs 2.1%, p < 0.001). HER2+ tumors had higher frequency of ERBB2mts compared to HER2- (4.3 vs 3%, p = 0.028). Tumors with score of 0 by immunohistochemistry demonstrated lower rate of ERBB2mts (0+ 2.2%, 1+ 3.5%, 2+ 4.5%, 3+ 3.45%, p < 0.05). Among HER2- tumors, ERBB2mts were present in 3.6% of hormone receptor (HR)+/HER2- & 1.9% of TNBC. Metastatic tumors had a higher rate of ERBB2mts compared to locoregional breast tumors (3.8 vs 2%, p < 0.001), with increased rates of activating mutations S310F (0.1 vs 0.0%, p < 0.05) & D769H (0.3 vs 0.1%, p < 0.05), & the resistance mutation L755S (1.2 vs 0.6%, p < 0.01). Compared to ERBB2-WT, ERRB2mts were associated with decreased ERBB2 transcripts levels in HER2+ samples (222 vs 441 transcripts per million [TPM], p < 0.001) & increased levels in HER2- samples (73 vs 35 TPM, p < 0.001). High tumor mutational burden (≥ 10 mut/Mb) & ERBB3 mutations were more common in ERBB2mts compared to ERRB2-WT (16.7 vs 7.7%, p < 0.001; 10.6 vs 0.8%, p < 0.001). ERBB2 fusions were rare (0.49%) with 97% occurring in HER2+ tumors. Of 8358 pts with outcome data, prognosis (HR 1.2, P = 0.06) & response to chemotherapy (HR 1.1, P = 0.42) was similar between pts with HER2- ERBB2mt & ERBB2-WT. Conclusions: ERBB2mts & fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, & lobular histology tumors - & did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy & may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts & clinical outcomes from this approach are under investigation.
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Ward, Elspeth, Anna Blümel, Emer Conroy, Grainne Cremin, Binbin Gao, William Gallagher, Idalia Cruz et al. "Abstract PD14-07: Bromodomain and Extra-Terminal motif (BET) inhibitors are a rational therapeutic choice for treatment of invasive lobular carcinoma". Cancer Research 82, n.º 4_Supplement (15 de febrero de 2022): PD14–07—PD14–07. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd14-07.
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Abstract Invasive lobular carcinoma (ILC) is the second most common type of breast cancer accounting for approximately 10-15% of all breast tumours. ILC is characterized by inactivation of E-Cadherin and cancer cells that invade the stroma in a "single-file" pattern. Women with ILC are more likely to have hormone receptor-positive disease. ILCs are three times more likely to metastasize to the peritoneum, gastrointestinal tract, and ovaries. ILC are currently treated in the same manner as all other ER+ breast cancers. Like invasive ductal carcinoma (IDC), anti-estrogen resistance has emerged as a significant problem in the management of ILC. Approximately half of the recurrences of ER+ breast tumors respond to anti-endocrine treatment, while the other half are resistant. Additionally, anti-estrogen-resistant breast tumor cells appear to have/acquire a more aggressive, invasive phenotype compared to their anti-estrogen-responsive counterparts. ILC is considered to be chemo-resistant and ILC patients receive no additional benefit from adjuvant chemotherapy. As such, there is a pressing need to develop tailored therapeutic options for endocrine-resistant ILC patients. The bromodomain and extra-terminal (BET) motif family are epigenetic readers that bind to acetylated histones, recruiting co-factors to regulate transcription. As part of the FP7 RATHER project aimed at identifying rational treatment options for ILC, we discovered that BRD3 (uniquely among the BET family members) is a marker of poor prognosis in ILC but not in ER+ breast cancers as a whole. We subsequently validated this in an independent cohort from the METABRIC study. These data suggest that Brd3 may play a significant role in tumour progression in ILC and may be a rational therapeutic target for lobular tumours. Using the two ILC cell lines SUM44PE (SUM44) and MDA MB 134 VI (MM134) previously shown to be anti-endocrine resistant we assessed the therapeutic potential of BET inhibition. We found that ILC cell lines that do not respond to anti-endocrine therapy are sensitive to a panel of BET inhibitors in both 2D and 3D assays. In particular the BET inhibitors JQ1 and Mivebresib had the highest potency, these BET inhibitors were selected for further research. Next, a multi-omics approach merging RNA-sequencing with mass spectrometry was utilised to dissect the transcriptional networks employed by BET inhibitors in this ILC setting. RNA-sequencing revealed dysregulated pathways in cell cycle division, DNA damage, apoptosis and MAPK signalling following treatment. Further, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was carried out to find the binding partners of the BRD proteins. Integrated pathway analysis through Genome Enhancer was used to assess the master regulators (MTRs) which drive BET inhibitor function. There was 142 MTRs found across the two cell lines treated with both inhibitors. Of note the MTR, FGFR3, was shown to regulate the downstream targets of both BET inhibitors. Further analysis of BET inhibition combined with erdafitinib, an FGFR inhibitor, drives increased cell inhibition compared to either agent alone. Finally, the efficacy of JQ1 in targeting ILC was assessed in vivo. We utilised the ILC cell-derived xenograft (CDX) models established by mammary intraductal implantation. The efficacy of BET inhibition alone and in combination with anti-endocrine therapies, tamoxifen and fulvestrant were assessed in the MM134 cell line. We found that JQ1 works synergistically with tamoxifen to significantly decrease tumour burden and metastatic potential in this tamoxifen resistant ILC model. Taken together this data highlights the need for tailored therapeutics in ILC research and highlights the use of BET inhibition in the anti-endocrine resistant ILC setting. Citation Format: Elspeth Ward, Anna Blümel, Emer Conroy, Grainne Cremin, Binbin Gao, William Gallagher, Idalia Cruz, Leena Hilakivi-Clarke, George Sflomos, Cathrin Brisken, Darran O'Connor. Bromodomain and Extra-Terminal motif (BET) inhibitors are a rational therapeutic choice for treatment of invasive lobular carcinoma [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-07.
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Carbognin, Luisa, Michele Simbolo, Caterina Vicentini, Isabella Sperduti, Anna Caliò, Francesco Schettini, Maria Vittoria Dieci et al. "Next-generation targeted sequencing (NGTS) investigating CDK4 as a prognostic driver in pure invasive lobular breast carcinoma (ILC): Preliminary results in early-stage patients (pts) stratified according to a validated clinico-pathological model." Journal of Clinical Oncology 36, n.º 15_suppl (20 de mayo de 2018): 542. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.542.
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Louie, Anna D., Rani Chudasama, Sharon Wu, Marzia Capelletti, Daniel Magee, W. Michael Korn, Virginia Kaklamani et al. "Abstract PD6-04: Mutational landscape and immune infiltration of breast cancer metastases to gynecologic and other organs". Cancer Research 82, n.º 4_Supplement (15 de febrero de 2022): PD6–04—PD6–04. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd6-04.
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Abstract Introduction: Breast cancer metastases (BCM), which cause most breast cancer (BC)-associated mortality, have increased genetic complexity compared to early-stage disease. However, the contribution of genetic alterations to site of BCM is not well-understood. Different breast cancer subtypes have varying patterns of BCM, e.g., lobular carcinoma more frequently spreads to gynecologic (Gyn) organs and the GI tract, perhaps hinting at selection pressures wherein some organs are hospitable to tumors with certain genetic alterations. Methods: Relationships between BCM site and mutations detected by DNA next-generation sequencing (NGS; NextSeq 592 gene panels or NovaSeq whole exome sequencing) were investigated using 12,464 BC samples sequenced at Caris Life Sciences (sample sizes, Table 1). PD-L1 expression was tested through IHC (Clone SP-142 (cut-off ≥1, 1%)). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high ≥ 10 mutations per MB). Immune cell fractions were calculated by deconvolution of whole-transcriptome data (NovaSeq) using Quantiseq (reference). Statistical significance was determined using chi-square and Wilcoxon rank sum tests adjusted for multiple comparisons. Results: Compared to primary breast tumors, BCM had increased frequency of TMB-H (10.08% vs. 4.94%), decreased PD-L1 positivity (21.09% vs. 35.82%), and were enriched for PIK3CA (34.62% vs 30.53%) and ESR1 mutations (13.34% vs 2.17%) (all P<0.001). PD-L1 positivity was highest in BCM to lymph nodes (43.06%) and axilla (39.77%). BCM to Gyn organs had more lobular histology, the highest rate of hormone receptor (HR)+ tumors (77.17%), and rarely had high TMB (6.73%) or were PD-L1 positive (11.39%). Double dendrogram hierarchical clustering of BCM site by mutation frequency and pathway alterations revealed BCM to Gyn organs as a simplicifolious clade with a unique mutational pattern. Compared to BC in breast, BCM to Gyn organs had higher rates of mutations of PIK3CA, AKT1, and BRAF; more mutations in DNA repair (0.79% vs 0.06%), transcription factor (4.72% vs 0.93%), and Wnt signaling pathways (2.36% vs 1.47%); but no increase in BRCA mutations. BCM to brain had the most p53 pathway and homologous recombination (HR) pathway mutations (64.71% and 14.01%), while Gyn had the least (19.69% and 7.09%). Quantiseq RNA deconvolution revealed differences in tumor immune cell infiltrate by BCM site. Gyn metastases vs breast tumors had increased B cells (6.20% vs 5.40%), M2 macrophages (5.71% vs 4.07%), and NK cells (3.82% vs 3.18%) (all P<0.01) and a M2/M1 macrophage ratio of 22.8:1 vs 1.3:1. Conclusions: BCM to Gyn organs have a unique mutational and immune suppression profile. Integrating the profiling with clinical outcomes may extend this prognostic signature and set the stage for improved treatment strategies for these patients. Confirmation from matched or sequential specimens could clarify tumor evolution. Our data support repeat biopsy of Gyn site metastases since more targetable mutations might be revealed. Targeting mechanisms of immunosuppression in Gyn BCM could expand therapeutic options. Table 1.Breast Cancer TumorsTumor SiteTotalPredominant Breast Cancer SubtypeAll12464HR+/HER2- (51.6%)Breast5014HR+/HER2- (46.5%)Liver2003HR+/HER2- (63.3%)Bone1132HR+/HER2- (69.4%)Axilla1051HR+/HER2- (47.7%)Lung823HR+/HER2- (46.1%)Lymph Node647HR+/HER2- (43.4%)Chest/Chest Wall375HR+/HER2- (44.8%)Brain359TNBC (38.2%)Other315HR+/HER2- (57.1%)Skin282HR+/HER2- (50.7%)Connective Tissue193HR+/HER2- (51.8%)GI Organs143HR+/HER2- (69.9%)Gynecologic Organs127HR+/HER2- (76.4%) Citation Format: Anna D Louie, Rani Chudasama, Sharon Wu, Marzia Capelletti, Daniel Magee, W. Michael Korn, Virginia Kaklamani, Antoinette R Tan, Pavani Chalasani, Wafik S El-Deiry, Don Dizon, Stephanie L. Graff. Mutational landscape and immune infiltration of breast cancer metastases to gynecologic and other organs [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-04.
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Sturgill, Emma G., Amanda Misch, Rebecca Lachs, Carissa C. Jones, Dan Schlauch, Suzanne F. Jones, Mythili Shastry et al. "Next-Generation Sequencing of Patients With Breast Cancer in Community Oncology Clinics". JCO Precision Oncology, n.º 5 (agosto de 2021): 1297–311. http://dx.doi.org/10.1200/po.20.00469.
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PURPOSE Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results. METHODS We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics. RESULTS The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor–positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1. Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways. CONCLUSION Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone.
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Krishnan, Preethi, Sunita Ghosh, Bo Wang, Mieke Heyns, Kathryn Graham, John R. Mackey, Olga Kovalchuk y Sambasivarao Damaraju. "Profiling of Small Nucleolar RNAs by Next Generation Sequencing: Potential New Players for Breast Cancer Prognosis". PLOS ONE 11, n.º 9 (15 de septiembre de 2016): e0162622. http://dx.doi.org/10.1371/journal.pone.0162622.
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Huang, Xin, Huanwen M. Wu, Changbin Zhu, Di Shao, Dan Guo, Yidong Zhou, Yan Lin et al. "Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): 558. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.558.
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558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]
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Uji, Kumiko, Yasuto Naoi, Naofumi Kagara, Masafumi Shimoda, Atsushi Shimomura, Naomi Maruyama, Kenzo Shimazu, Seung Jin Kim y Shinzaburo Noguchi. "Significance of TP53 mutations determined by next-generation “deep” sequencing in prognosis of estrogen receptor-positive breast cancer". Cancer Letters 342, n.º 1 (enero de 2014): 19–26. http://dx.doi.org/10.1016/j.canlet.2013.08.028.
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Batista, Marta Vaz, Diogo Alpuim Costa, Paula Borralho y Sofia Braga. "Next-Generation Sequencing in Breast Cancer Management: A Case Report of Genomic Tumour Evolution over Time". Case Reports in Oncology 14, n.º 2 (16 de agosto de 2021): 1212–19. http://dx.doi.org/10.1159/000517441.
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The clinicopathological breast cancer subtypes are used in clinical practice to better anticipate biological behaviour and guide systemic treatment strategy. In the adjuvant setting, genomic assay recurrence scores became widely available for luminal-like disease. Recently, next-generation sequencing (NGS) platforms have been used, essentially, in more advanced disease setting, in situations refractory to conventional treatment, or even in rare cancers for which there are no established treatment guidelines. Moreover, subpopulations of cancer cells with unique genomes within the same patient may exist across different regions of a tumour or evolve over time, which is called intratumoural heterogeneity. We herein report a case of a 38-year-old woman with breast cancer whose primary and metastatic disease exhibited discordant expression of hormone receptors, with the former being positive and the latter negative. Furthermore, the NGS analysis revealed slight and dynamic changes of mutational profiles between different metastatic lesions, potentially impacting breast cancer management and prognosis. These alterations may reflect tissular and temporal changes in tumour subclones and may also be due to the selective pressure caused by antineoplastic treatment. The use of genomic analyses in order to improve cancer treatment has been studied prospectively with encouraging results. The widespread use of NGS tests in clinical practice also creates new challenges. The most relevant may be to know which genomic alterations detected should be valued and how they should be targeted.
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Van Thuan, Tran, Nguyen Van Chu, Pham Hong Khoa, Nguyen Tien Quang, Dao Van Tu, Nguyen Thi Quynh Tho, Phung Thi Huyen et al. "A Novel BRCA1 Gene Mutation Detected With Breast Cancer in a Vietnamese Family by Targeted Next-Generation Sequencing: A Case Report". Breast Cancer: Basic and Clinical Research 14 (enero de 2020): 117822342090155. http://dx.doi.org/10.1177/1178223420901555.
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Hereditary breast cancer is an inherited genetic condition, mainly caused by BRCA1 and BRCA2 gene mutations. These genetic changes can increase the risks of breast and ovarian cancers in women, while prostate and breast cancers in men. Especially, mutations in either BRCA1 or BRCA2 genes take important roles in early-onset breast cancer. The present study focused on a 47-year-old Vietnamese woman with breast cancer by applying targeted next-generation sequencing technique. A novel BRCA1 gene mutation, namely NM_007294.3 (BRCA1): c.4998insA (p. Tyr1666Terfs), was identified both in this patient and in some of the members in her family proved the fact that the mutated genes passed down through generations. This change may exponentially initiate breast cancer risks and become a valuable marker for exact clinical prognosis and treatment.
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Schmidt, Marcus y Anne-Sophie Heimes. "Immunomodulating Therapies in Breast Cancer—From Prognosis to Clinical Practice". Cancers 13, n.º 19 (29 de septiembre de 2021): 4883. http://dx.doi.org/10.3390/cancers13194883.
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The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.
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Chang, Ya-Sian, Chieh-Min Chang, Chien-Yu Lin, Dy-San Chao, Hsi-Yuan Huang y Jan-Gowth Chang. "Pathway Mutations in Breast Cancer Using Whole-Exome Sequencing". Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 28, n.º 2 (27 de marzo de 2020): 107–16. http://dx.doi.org/10.3727/096504019x15698362825407.
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The genomic landscape of breast cancer (BC) is complex. The purpose of this study was to decipher the mutational profiles of Taiwanese patients with BC using next-generation sequencing. We performed whole-exome sequencing on DNA from 24 tumor tissue specimens from BC patients. Sanger sequencing was used to validate the identified variants. Sanger sequencing was also performed on paired adjacent nontumor tissues. After genotype calling and algorithmic annotations, we identified 49 deleterious variants in canonical cancer-related genes in our BC cohort. The most frequently mutated genes were PIK3CA (16.67%), FKBP9 (12.5%), TP53 (12.5%), ATM (8.33%), CHEK2 (8.33%), FOXO3 (8.33%), NTRK1 (8.33%), and NUTM2B (8.33%). Seven mutated variants (ATR p.V1581fs, CSF1R p.R579Q, GATA3 p.T356delinsTMKS, LRP5 p.W389*, MAP3K1 p.T918fs, MET p.K1161fs, and MTR p.P1178S) were novel variants that are not present in any gene mutation database. After grouping the samples according to molecular subtype, we found that the cell cycle, MAPK, and chemokine signaling pathways in the luminal A subtype of BC; the focal adhesion, axon guidance, and endocytosis pathways in the luminal B subtype; and amyotrophic lateral sclerosis in the basal-like subtype were exclusively altered. Survival curve analysis showed that the presence of the MAPK signaling pathway and endocytosis mutations were correlated with a poor prognosis. These survival data were consistent with cBioPortal analyses of 2,051 BC cases. We discovered novel mutations in patients with BC. These results have implications for developing strategic, adjuvant, and gene-targeted therapies.
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Christgen, Matthias, Stephan Bartels, Jana L. van Luttikhuizen, Janin Bublitz, Luisa U. Rieger, Henriette Christgen, Helge Stark et al. "E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements". Modern Pathology 33, n.º 12 (22 de junio de 2020): 2483–98. http://dx.doi.org/10.1038/s41379-020-0591-3.
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AbstractLoss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.
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He, Lin, Ellen Araj y Yan Peng. "HER2 Positive and HER2 Negative Classical Type Invasive Lobular Carcinomas: Comparison of Clinicopathologic Features". Current Oncology 28, n.º 3 (24 de abril de 2021): 1608–17. http://dx.doi.org/10.3390/curroncol28030150.
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Human epidermal growth factor receptor 2 (HER2) positive (+) classical type invasive lobular carcinoma (cILC) of the breast is extremely rare and its clinicopathologic features have not been well characterized. We compared features of HER2(+) and HER2 negative (−) cILCs. A total of 29 cases were identified from the clinical database at our institution from 2011-2019; 9 were HER2(+) cILC tumors and 20 were HER2(−) cILC tumors. The results reveal that HER2(+) cILC group had significantly increased Ki-67 expression and reduced estrogen receptor (ER) expression compared to HER2(−) cILC group (both p < 0.05). In addition, HER2(+) cILCs tended to be diagnosed at a younger age and more common in the left breast, and appeared to have a higher frequency of nodal or distant metastases. These clinicopathologic features suggest HER2(+) cILC tumors may have more aggressive behavior than their HER2(−) counterpart although both groups of tumors showed similar morphologic features. Future directions of the study: (1) To conduct a multi-institutional study with a larger case series of HER2(+) cILC to further characterize its clinicopathologic features; (2) to compare molecular profiles by next generation sequencing (NGS) assay between HER2(+) cILC and HER2(−) cILC cases to better understand tumor biology of this rare subset of HER2(+) breast cancer; and (3) to compare molecular characteristics of HER2(+) cILC and HER2(+) high grade breast cancer in conjunction with status of tumor response to anti-HER2 therapy to provide insight to management of this special type of low grade breast cancer to avoid unnecessary treatment and related toxicity
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Ignatova, A. V., A. M. Mudunov, S. О. Podvyaznikov y Yu V. Alymov. "Mammary analogue secretory carcinoma of the salivary gland with NTRK fusions: new approaches for diagnostics and targeted therapy (review)". Head and Neck Tumors (HNT) 10, n.º 2 (24 de julio de 2020): 69–78. http://dx.doi.org/10.17650/2222-1468-2020-10-2-69-78.
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Mammary analogue secretory carcinoma (MASC) of the salivary gland is a rare salivary cancer, histologically resembling to secretory carcinoma of the breast. In 2017 World Health Organization reported MASC is a new salivary cancer subtype. The aim of this article is to collect and analyze data about MASC, particularly clinical, histological and molecular profile, to evaluate targeted therapy effects. We discuss a case report of dramatic and durable response with entrectinib and the development of acquired resistance in an NTRK3-fusion positive salivary cancer, detected by next-generation sequencing. Next-generation sequencing as a comprehensive molecular profiling, that helps to investigate molecular profile of rare tumors and gives an opportunity to use an effective therapeutic options. Identifying ETV6-NTRK3 positive MASC provides a better prognosis for metastatic disease by using a novel effective targeted therapy with tyrosine kinase inhibitors (entrectinib, larotrectinib). Despite a durable and dramatic response, we showed an interesting case of the development of acquired resistance to tyrosine kinase inhibitors mediated by the appearance of a novel NTRK3 G623R mutation. Finally, we believe in great perspectives of comprehensive molecular profiling and targeted therapy for rare malignancies with NTRK gene fusions, including second-generation tyrosine kinase inhibitors.
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Ades, Felipe, Dimitrios Zardavas, Ivana Bozovic-Spasojevic, Lina Pugliano, Debora Fumagalli, Evandro de Azambuja, Giuseppe Viale, Christos Sotiriou y Martine Piccart. "Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives". Journal of Clinical Oncology 32, n.º 25 (1 de septiembre de 2014): 2794–803. http://dx.doi.org/10.1200/jco.2013.54.1870.
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Gene expression profiling has reshaped our understanding of breast cancer by defining and characterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor 2–enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has been reported to have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has a distinct profile of response to hormone therapy and chemotherapy. Although luminal cancers share similarities, the studies conducted in recent years using next-generation sequencing technology show that luminal A and B breast cancers should be perceived as distinct entities, with specific oncogenic drivers, rather than more proliferative varieties of luminal tumors. This review discusses the definition and molecular characterization of luminal B breast cancer and presents the available clinical evidence for chemotherapy and endocrine therapy patterns of response. It also provides an overview of ongoing research on molecularly targeted agents for this disease.
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Nagahashi, Masayuki, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Kazuhiro Yoshida, Takashi Kuwayama, Seigo Nakamura et al. "Comprehensive genomic sequencing for triple negative breast cancer in Japan." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e23122-e23122. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23122.
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e23122 Background: Breast cancer is the leading cancer among women both in US and Japan. Triple negative breast cancer (TNBC) is the subset of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and HER2. While the selective ER modulator tamoxifen or anti-HER2 therapy for breast cancer patients with ER positive or HER2 protein overexpression are the most successful examples of targeted therapies, only limited therapies are available for patients with TNBCs, which are associated with a poor prognosis. Advance in next-generation sequencing enables us to identify actionable driver mutations that can be potentially treated by targeted therapies in each cancer patient. The aim of this study is to examine actionable driver mutations in TNBCs in Japan by comprehensive genomic sequencing (CGS) with 435 gene panel, and compare the driver events in Japan with TCGA database to validate the utility of CGS. Methods: We examined all exons of 435 known cancer genes in Japanese TNBC patients (N = 53) by CGS and evaluated for concordance among independent data obtained from The Cancer Genome Atlas-TNBC whole exome sequencing database (N = 123). Results: Oncogenic driver mutations were identified in 51 of 53 Japanese patients (96%) with TNBC and 36 of 53 patients (67%) harbored mutations in genes associated with FDA-approved targeted therapies, indicating the potential clinical utility of a large gene panel for evaluating patients with TNBC. Among 80 total genetic alterations, frequently mutated genes ( > 10% patients) were TP53, PIK3CA and PTEN. Overall, the mutation spectrum of the Japanese patients is similar to that of the TCGA population, except amplification of MYC. Conclusions: Use of a CGS panel of 435 genes can reliably identify all of the critical mutations in TNBC patients, which are similar as TCGA data. The information derived from CGS can be used to determine the optimal treatment for TNBC patients.
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Liu, Yuhong, Yixiang Gan, NiJiati AiErken, Wei Chen, Shiwei Zhang, Jie Ouyang, Leli Zeng y Di Tang. "Combining Organoid Models with Next-Generation Sequencing to Reveal Tumor Heterogeneity and Predict Therapeutic Response in Breast Cancer". Journal of Oncology 2022 (22 de agosto de 2022): 1–13. http://dx.doi.org/10.1155/2022/9390912.
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Estrogen receptor-positive (ER+) breast cancer (BC) is a common subtype of BC with a relatively good prognosis. However, recurrence and death from ER+ BC occur because of tumor heterogeneity. This study aimed to explore tumor heterogeneity using next-generation sequencing (NGS) and tumor-organoid models to promote BC precise therapy. We collected needle biopsy, surgical excision, and cerebrospinal fluid (CSF) samples to establish tumor organoids. We found that the histological characteristics of organoids were consistent with original lesions and recapitulated their heterogenicity. In addition, the NGS results showed that PIK3CA and TP53 genes had detrimental mutations. BAP1, RET, AXIN2, and PPP2R2A genes had mutations with unknown function. The score for homologous recombination deficiency (HRD) of genome was 56, indicating that the tumor was likely sensitive to PARPi. The mutant-allele tumor heterogeneity (MATH) value of the tumor genome was 68.03, indicating high tumor heterogeneity. At last, we performed a drug screening on organoids. The toxicity of different drugs toward BC organoids originated from needle biopsy and surgical excision was tested, respectively. The IC50 values in the needle biopsy groups were paclitaxel 2.83 μM, carboplatin 61.47 μM, neratinib 0.8 μM, lapatinib >100 μM; in the surgical excision groups: trastuzumab >100 μM, docetaxel 0.036 μM, tamoxifen 20.54 μM, olaparib 5.478 μM, BYL719 < 0.1 μM. The toxicity data showed that the BC organoids could show dynamic characteristics of tumor progression and reflect the heterogeneity of BC. Our study demonstrates that the combined use of tumor organoids and NGS is a potential way to test tumor heterogeneity and predict drug response in ER + BC, which contributes to the development of personalized therapy.
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Jancalek, Radim, Marek Vecera, Frantisek Siegl, Jiri Sana, Karolina Trachtova, Michal Hendrych, Vaclav Vybihal et al. "PATH-02. ANALYSIS OF MICRORNA EXPRESSION IN BRAIN METASTASES USING NEXT-GENERATION SEQUENCING". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii149—vii150. http://dx.doi.org/10.1093/neuonc/noac209.575.
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Abstract BACKGROUND Brain metastases (BMs) are intracranial tumors that frequently occur in adult cancer patients. Because the prognosis of patients with BM individually varies, it would be useful to improve prognostic scoring tools by including new high-performance biomarkers. MicroRNAs (miRNAs) appear to be promising in this regard as they are highly stable and, thus, suitable for both next-generation sequencing (RNA-Seq) and retrospective analyses in formalin-fixed and paraffin-embedded (FFPE) tissues.Material and METHODS Total RNA enriched for miRNAs was isolated from 71 freshly frozen histopathologically confirmed BMs with origin in 5 tumor types (ca lung - 37%, melanoma - 23%, ca breast - 18%, RCC - 15%, CRC - 7%) using mirVana miRNA Isolation Kit (Thermo Fisher Scientific). Sequencing libraries were prepared from RNA using the QIAseq miRNA Library Kit (Qiagen) and sequenced using the NextSeq 500 platform (Illumina). The miRNA molecules were subsequently transcribed from total RNA samples isolated from a retrospective set of 119 FFPE tissues using the TaqMan Advanced miRNA cDNA Synthesis Kit, and the expression of selected miRNAs was validated in a pilot experiment by qPCR using TaqMan Fast Advanced Master Mix and appropriate TaqMan MicroRNA Assays (all from Thermo Fisher Scientific). RESULTS The differential analysis identified 373 miRNAs with significantly different expression among the 5 BMs groups (p< 0.001). A molecular classifier based on the expression of 32 miRNAs was able to classify all samples correctly. Out of these, seven, including miR-122-5p, miR-141-3p, miR-146a-5p, miR-194-5p, miR-200c-3p, miR-211-3p, and miR-215-5p, were chosen for subsequent validation and their significantly different expression in 5 BMs groups was validated. CONCLUSIONS Presented results confirm the importance of studying dysregulated miRNA expression in BM and the diagnostic potential of validated miRNAs. The study was prepared with the grant support of the Ministry of Health of the Czech Republic - grant No. NV18-03-00398.
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Carbognin, Luisa, Michele Simbolo, Anna Caliò, Caterina Vicentini, Pietro Delfino, Isabella Sperduti, Matteo Fassan et al. "Targeted next-generation sequencing identifies genomic abnormalities potentially driving the prognosis of early-stage invasive lobular breast carcinoma patients stratified according to a validated clinico-pathological model". Breast 50 (abril de 2020): 56–63. http://dx.doi.org/10.1016/j.breast.2020.01.034.
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Li, Shunying, Hongna Lai, Jieqiong Liu, Yujie Liu, Liang Jin, Yudong Li, Fengtao Liu et al. "Circulating Tumor DNA Predicts the Response and Prognosis in Patients With Early Breast Cancer Receiving Neoadjuvant Chemotherapy". JCO Precision Oncology, n.º 4 (septiembre de 2020): 244–57. http://dx.doi.org/10.1200/po.19.00292.
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PURPOSE Many patients with breast cancer still relapse after curative treatment. How to identify the ones with high relapse risk remains a critical problem. Circulating tumor DNA (ctDNA) has recently become a promising marker to monitor tumor burden. Whether ctDNA can be used to predict the response and prognosis in patients with breast cancer receiving neoadjuvant chemotherapy (NAC) is unknown. Our study aimed to evaluate the clinical value of the presence and dynamic change of ctDNA to predict the tumor response and prognosis in patients with breast cancer treated with NAC. MATERIALS AND METHODS Fifty-two patients with early breast cancer who underwent NAC were prospectively enrolled. Serial plasma samples before, during, and after NAC and paired tumor biopsies were harvested and subjected to deep targeted sequencing using a large next-generation sequencing panel that covers 1,021 cancer-related genes. RESULTS Positive baseline ctDNA was detected in 21 of 44 patients before NAC. Most patients with positive ctDNA had one or more mutations confirmed in paired primary tumor. The ctDNA level after 2 cycles of NAC was predictive of local tumor response after all cycles of NAC (area under the curve, 0.81; 95% CI, 0.61 to 1.00). ctDNA tracking during NAC outperformed imaging in predicting the overall response to NAC. More importantly, positive baseline ctDNA is significantly associated with worse disease-free survival ( P = .011) and overall survival ( P = .004) in patients with early breast cancer, especially in estrogen receptor–negative patients. CONCLUSION Our study demonstrated that ctDNA can be used to predict tumor response to NAC and prognosis in early breast cancer, providing information to tailor an individual’s therapeutic regimen.
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Sekkate, Sakina, Laure Ladrat, Christelle Pouliquen, Celine Callens, Jean Francois Geay y Philippe Beuzeboc. "Neuroendocrine differentiation in metastatic breast cancer following CDK 4/6 inhibitors." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): e13029-e13029. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13029.
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e13029 Background: First-line treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor for HR+/HER2- postmenopausal metastatic breast cancer (mBC) is considered as a standard of care based on the compelling data across all landmark trials. Methods: We report our experience about two cases with metastatic breast cancer treated by CDK4/6 inhibitor in combination with an aromatase inhibitor, which develop neuroendocrine differentiation. After observing an unusual massive progression, a biopsy of the metastasis was performed in both patients. Both histological analysis confirmed a lobular breast cancer with small cell neuroendocrine features and a high proliferation index (KI 67 90%). An NGS (Next generation sequencing) profile was realized on primary and metastatic tumors to detect new acquired genomic alterations. Results: The comparative analysis of the NGS results of primary and metastatic tumors revealed the occurrence of several events in both patients under treatment. For one patient, we identified new mutations in the genes CDH1, FANCG, PIK3CA, PTEN and TP53, which did not exist initially. For the second patient, we found an amplification of the segment containing FGFR1, CCND1, FGF4, FGF3, FADD genes and the deletion of the segment containing RB1 andTP53 genes. Such events were not observed on the primary tumor. Conclusions: Prostate adenocarcinoma may develop neuroendocrine features in later stages of castration-resistant prostate cancer but neuroendocrine differentiation is atypical in breast carcinoma. In case of unusual rapidly progressive disease after CDK4/6 inhibitor, biopsy of new metastases should be recommanded to search neuroendocrine differentiation, or druggable mutations to guide the treatment.
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Grogan, Nicole Margo, Yi-Mi Wu, Dan R. Robinson, James M. Rae, Norah Lynn Henry, Daniel F. Hayes, Michelle F. Jacobs et al. "Use of comprehensive next-generation sequencing to identify pathogenic germline variants with therapeutic relevance in metastatic breast cancer." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): 10527. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.10527.
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10527 Background: Among patients with early-stage breast cancer, approximately 6-10% have a pathogenic germline variant (PGV) conferring inherited cancer predisposition. In contrast, few studies have explored the frequency and types of PGVs identified in patients with metastatic breast cancer (MBC); therefore, additional data is needed. Methods: From 2011-2020, 278 patients with MBC underwent fresh tumor biopsy and blood sample collection for paired tumor/normal DNA (targeted exome capture with analysis of 1700 genes) and RNA (tumor transcriptome) sequencing through the Michigan Oncology Sequencing (Mi-ONCOSEQ) program. Somatic and germline alterations were annotated and classified according to degree of clinical actionability with results returned to treating oncologists. Retrospective chart review was performed to determine if: 1) a PGV was identified prior to Mi-ONCOSEQ testing, 2) patients met National Comprehensive Cancer Network (NCCN) guideline criteria for genetic testing on the basis of personal or family cancer history and 3) patients received subsequent therapy informed by a PGV. Results: Forty-eight of the 278 patients (17.3%) had at least one PGV identified, with a total of 50 PGVs identified in this cohort. Only twelve of these PGVs (24%) had been identified prior to Mi-ONCOSEQ testing. The most frequent PGVs identified were in CHEK 2 (n = 9, 18%), MUTYH (n = 6, 12%), BRCA 1 (n = 5, 10%), BRCA2 (n = 5, 10%), ATM (n = 4, 8%) and PALB2 (n = 4, 8%). Somatic loss of heterozygosity events (LOH) occurred in 30 of the 50 cases with PGVs identified (60%). LOH events were observed in 83.3% of BRCA1, BRCA2, ATM and PALB2 PGVs, but were less frequently observed with CHEK2 (33.3%) and MUTYH (66.7%). Two hundred sixteen out of 278 patients (77.7%) in this cohort met NCCN criteria for genetic testing, although six patients with a PGV identified (CHEK2: n = 5; MUTYH: n = 1) did not meet NCCN criteria. Twenty-nine PGVs identified (58%) had potential therapeutic relevance and 11 patients (22.9%) received targeted therapy based on the PGV. Conclusions: The frequency of PGVs identified in this cohort is nearly double the frequency reported for patients with early-stage disease, suggesting that certain PGVs may confer worse prognosis. CHEK2, the most frequently identified PGV, was less likely to have an identifiable LOH event. The direct role of CHEK2 PGVs in tumor pathogenesis is uncertain, but other mechanisms of silencing the wild type allele must be considered. Despite the majority of patients meeting NCCN criteria for genetic testing, those with PGVs in CHEK2 were less reliably identified by this mechanism. The majority of PGVs identified were of potential therapeutic relevance, supporting the recommendation for genetic testing in all patients with MBC.
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Pizzuti, Laura, Eriseld Krasniqi, Chiara Mandoj, Daniele Marinelli, Domenico Sergi, Elisabetta Capomolla, Giancarlo Paoletti et al. "Observational Multicenter Study on the Prognostic Relevance of Coagulation Activation in Risk Assessment and Stratification in Locally Advanced Breast Cancer. Outline of the ARIAS Trial". Cancers 12, n.º 4 (1 de abril de 2020): 849. http://dx.doi.org/10.3390/cancers12040849.
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A hypercoagulable state may either underlie or frankly accompany cancer disease at its onset or emerge in course of cancer development. Whichever the case, hypercoagulation may severely limit administration of cancer therapies, impose integrative supporting treatments and finally have an impact on prognosis. Within a flourishing research pipeline, a recent study of stage I-IIA breast cancer patients has allowed the development of a prognostic model including biomarkers of coagulation activation, which efficiently stratified prognosis of patients in the study cohort. We are now validating our risk assessment tool in an independent cohort of 108 patients with locally advanced breast cancer with indication to neo-adjuvant therapy followed by breast surgery. Within this study population, we will use our tool for risk assessment and stratification in reference to 1. pathologic complete response rate at definitive surgery, intended as our primary endpoint, and 2. rate of thromboembolic events, intended as our secondary endpoint. Patients’ screening and enrollment procedures are currently in place. The trial will be shortly enriched by experimental tasks centered on next-generation sequencing techniques for identifying additional molecular targets of treatments which may integrate current standards of therapy in high-risk patients.
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Herrera Juarez, Mercedes, Pablo Tolosa Ortega, Ana Sanchez de Torre y Eva Ciruelos Gil. "Biology of the Triple-Negative Breast Cancer: Immunohistochemical, RNA, and DNA Features". Breast Care 15, n.º 3 (2020): 208–16. http://dx.doi.org/10.1159/000508758.
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Background: The triple-negative breast cancer (TNBC) constitutes a heterogeneous disease with an aggressive behavior and a poor prognosis. A better understanding of its biology is required to identify new biomarkers and improve clinical outcomes. Summary: To date, the definition and classification of TNBC depends on a multiomic approach including immunohistochemistry (IHC), genomic, and transcriptomic features, and the tumor immune landscape. The development of new technologies has allowed us to sequence the whole cancer genome. The Cancer Genome Atlas (TCGA) and next-generation sequencing have led to a greater knowledge of DNA alterations such as TP53 or BRCA mutations, copy number variations, and DNA methylations. In addition, gene expression profiling has allowed to define a molecular intrinsic classification of TNBC based on mRNA. IHC and genomic profiling are also necessary to identify new immune biomarkers such as the presence of tumor-infiltrating lymphocytes and the expression of immune checkpoint molecules. Key Messages: This review aimed to provide recent knowledge of TNBC biology and classification focused on IHC, transcriptomics, genomic features, and the new immune biomarkers.
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Ellsworth, Darrell L., Clesson E. Turner y Rachel E. Ellsworth. "A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements". Journal of Oncology 2019 (9 de julio de 2019): 1–10. http://dx.doi.org/10.1155/2019/4382606.
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Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.
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Hlaváč, Viktor, Radka Václavíková, Veronika Brynychová, Renata Koževnikovová, Katerina Kopečková, David Vrána, Jiří Gatěk y Pavel Souček. "Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response". International Journal of Molecular Sciences 21, n.º 24 (15 de diciembre de 2020): 9556. http://dx.doi.org/10.3390/ijms21249556.
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Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations.
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Afkhami, Michelle, Idoroenyi Usua Amanam, Patricia A. Aoun, Dan Schmolze, Susan Yost, Paul Henry Frankel, Kim Nguyen, Wai (Kim) Wai Yu, Thehang H. Luu y Yuan Yuan. "Genomic profiling of metaplastic breast cancer: A single center experience." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e12041-e12041. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12041.
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e12041 Background: Metaplastic breast cancer (MpBC) is a rare malignancy with aggressive clinical presentation and poor prognosis. The goal of this study is to characterize MpBC at the genomic level with targeted exome sequencing and correlate with clinical-pathological characteristics. Methods: We have Identified 23 patients (pts) with a diagnosis of MpBC through the COH Cancer Registry from 1995 to 2013. A next generation sequencing based panel (Onco48) was performed on 21 pts on using the Ion AmpliSeq™ Kit. Molecular testing for two pts was performed at FoundationOne®. Patient’s clinical-pathological characteristics were also captured (age, race, stage, chemotherapy, radiation therapy history, and 5-year relapse free survival (RFS)). Results: Of the 21 specimens tested with COH Onco48, 3 failed to yield results. Of the 20 pts included in the analysis, 1 pt did not have survival information available. The median age at time of diagnosis was 68 years (range 35-93). All of the tumors were TNBC. The subtypes of MpBC were: squamous (35%), spindle (30%), mixed squamous and spindle (15%) and chondroid (20%). A total of 70% of pts received (neo)adjuvant chemotherapy, and 65% received radiation therapy. Median follow-up of alive pts is 63 months. Median RFS and OS have not been reached for entire cohort with a lower 95% of PFS of 22.2 months. The most commonly mutated genes included TP53 (65%), PIK3CA (45%), PTEN (15%).In a univariate analysis, the association of p53, PTEN, PIK3CA mutations and breast cancer specific survival. RFS at 2 years was 33% (0.03-0.64) for those with PIK3CA mutations, and 100% for those without (p<0.01, log-rank). Overall survival was 56% at 2 years in pts with PIK3CA mutations (95% CI 0.23-0.88) compared with 100% in pts without PIK3CA mutations (p<0.02). There are no statistically significant association between P53, PTEN mutation and survival. Conclusions: PIK3CA mutation confers poor prognosis in this small cohort of patients with MpBC. A larger cohort of pts is needed to verify these findings.
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Hlaváč, Viktor, Radka Václavíková, Veronika Brynychová, Pavel Ostašov, Renata Koževnikovová, Katerina Kopečková, David Vrána, Jiří Gatěk y Pavel Souček. "Role of Genetic Variation in Cytochromes P450 in Breast Cancer Prognosis and Therapy Response". International Journal of Molecular Sciences 22, n.º 6 (10 de marzo de 2021): 2826. http://dx.doi.org/10.3390/ijms22062826.
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Breast cancer is the most frequent cancer in the female population worldwide. The role of germline genetic variability in cytochromes P450 (CYP) in breast cancer prognosis and individualized therapy awaits detailed elucidation. In the present study, we used the next-generation sequencing to assess associations of germline variants in the coding and regulatory sequences of all human CYP genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 22 prioritized variants associating with a response or survival in the above evaluation phase were then analyzed by allelic discrimination in the large confirmation set (n = 802). Associations of variants in CYP1B1, CYP4F12, CYP4X1, and TBXAS1 with the response to the neoadjuvant cytotoxic chemotherapy were replicated by the confirmation phase. However, just association of variant rs17102977 in CYP4X1 passed the correction for multiple testing and can be considered clinically and statistically validated. Replicated associations for variants in CYP4X1, CYP24A1, and CYP26B1 with disease-free survival of all patients or patients stratified to subgroups according to therapy type have not passed a false discovery rate test. Although statistically not confirmed by the present study, the role of CYP genes in breast cancer prognosis should not be ruled out. In conclusion, the present study brings replicated association of variant rs17102977 in CYP4X1 with the response of patients to the neoadjuvant cytotoxic chemotherapy and warrants further research of genetic variation CYPs in breast cancer.
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Chen, Xinxin, Lehong Zhang, Min Yuan, Ziqiao Kuang, Ying Zou, Tian Tang, Wangjian Zhang et al. "Sam68 Promotes the Progression of Human Breast Cancer through inducing Activation of EphA3". Current Cancer Drug Targets 20, n.º 1 (27 de enero de 2020): 76–83. http://dx.doi.org/10.2174/1568009619666190718124541.
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Background: Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer. Materials and Methods: The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68. Results: Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer. Conclusion: High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.
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Caparica, Rafael, Matteo Lambertini, Noam Pondé, Debora Fumagalli, Evandro de Azambuja y Martine Piccart. "Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives". Therapeutic Advances in Medical Oncology 11 (enero de 2019): 175883591982771. http://dx.doi.org/10.1177/1758835919827714.
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Achieving a pathologic complete response after neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial demonstrated a significant survival improvement with capecitabine in patients with residual invasive disease after neoadjuvant chemotherapy, and the KATHERINE trial showed a significant benefit of trastuzumab-emtansine (TDM1) in human epidermal growth factor receptor 2 (HER2)-positive patients who did not achieve a pathologic complete response after neoadjuvant treatment, creating interesting alternatives of post-neoadjuvant treatments for high-risk patients. New agents are arising as therapeutic options for metastatic breast cancer such as the cyclin-dependent kinase inhibitors and the immune-checkpoint inhibitors, but none has been incorporated into the post-neoadjuvant setting so far. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our knowledge regarding the biology of residual disease, and also on the mechanisms involved in treatment resistance. The present manuscript reviews the current available strategies, the ongoing trials, the potential biomarker-guided approaches and the perspectives for the post-neoadjuvant treatment and the management of residual disease after neoadjuvant treatment in breast cancer.
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Meric-Bernstam, Funda, Xiaofeng Zheng, Maryam Shariati, Senthil Damodaran, Chetna Wathoo, Lauren Brusco, Mehmet Esat Demirhan et al. "Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer". JCO Precision Oncology, n.º 2 (noviembre de 2018): 1–15. http://dx.doi.org/10.1200/po.17.00245.
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Purpose To determine the significant genomic alterations in patients with metastatic breast cancer (MBC) and survival outcomes in common genotypes. Patients and Methods High-depth next-generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 with estrogen receptor/progesterone receptor–positive and human epidermal growth factor receptor 2 (HER2 [hormone receptor positive (HR+)])–positive, 32 with HER2-positive, and 60 with triple-negative (estrogen receptor/progesterone receptor–negative and HER2-negative) disease. Kaplan-Meier survival analysis was performed in the discovery set, in patients with breast cancer analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. Results Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was an SMG in all three subtypes. The most SMGs in patients with HR+ cancer were PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival ( P = .004), progression-free survival ( P < .001), and overall survival ( P = .003). Furthermore, TP53 status was prognostic among patients with HR+ cancer with PIK3CA mutations. TP53 mutations were associated with poorer overall survival in the 442 patients with HR+ breast cancer analyzed in The Cancer Genome Atlas ( P = .042) and in an independent set of 96 patients with HR+ MBC who underwent clinical sequencing ( P < .001). Conclusion SMGs differ by tumor subtype, but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer and should be considered in the design and interpretation of precision oncology trials.
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Kuo, Sung Hsin, Po-Han Lin, Shi-Yi Yang y Chiun-Sheng Huang. "Association of discovered novel SNPs of FGFR2 and MAP3K1 genes from next-generation sequencing with the prognosis of hormone receptor-positive early breast cancer patients." Journal of Clinical Oncology 34, n.º 15_suppl (20 de mayo de 2016): e12054-e12054. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.e12054.
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Cosentino, Dorian y Maria Carla Valli. "Clinical Application of Integrated Treatments in Breast Cancer". Tumori Journal 84, n.º 2 (marzo de 1998): 223–28. http://dx.doi.org/10.1177/030089169808400221.
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In this paper we analyse the problems related to the “state of the art” in the treatment of stage I and II breast cancer which has become, in Italy too, an increasingly prominent problem: it is the most frequently diagnosed female cancer, accounting for about 45,000 new cases/year (150/100,000 women). In the last decade the approach to this disease has greatly evolved because of new surgical techniques, advances in adjuvant medical therapies, innovations in the field of radiotherapy, and wider use of biological parameters. We emphasize the emerging problem of ductal and lobular carcinoma in situ, because their biological patterns will be better indentified and the related treatment extensively practiced in the next future. The innovations in surgery, which has now a less demolishing role, are reviewed focusing on the “sentinel axillary node” and the actual need for axillary dissection. In relation to chemotherapy (CT), we evaluate the role of adjuvant treatment also in node negative patients, and the impact of neoadjuvant schedules on survival and toxicity. Radiotherapy (RT) is complementary to conservative surgery, and its important role in preventing local relapse and in increasing OS (overall survival) has been established; recent and more sophisticated techniques have reduced its acute and late toxicity. We are however waiting for answers concerning the usefulness of a booster dose, the impact of RT on local relapse in DCIS, and the impact of RT to the breast regional lymph nodes on OS and disease-free survival (DFS). The optimal sequencing and timing of postoperative RT and CT are unknown, both concerning each other and surgery. Some possibilities include giving all planned CT before RT, all CT after RT, giving both concurrently, or giving a portion of CT before RT and then completing CT afterwards (sandwich technique): we analyse the advantages and the problems of these different therapeutic schedules in relation to the OS, the DFS and cosmesis. In conclusion, there are very few certainties to guide us in the clinical practice: the general feeling is that we need to collect more data on homogeneous groups of patients to better understand which are the prognostic factors we can rely on, in order to choose the best treatment strategy, and which are the optimal schedules of adjuvant treatments (CT and RT), with the aim of improving OS, DFS and cosmesis.
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Basu, Gargi D., Tracey White, Janine R. LoBello, Ahmet Kurdoglu, Jeffrey M. Trent, Matthew J. Halbert, Thomas Royce y Joyce O'Shaughnessy. "Assessment of ESR1 and ERBB2 mutations in estrogen receptor positive (ER+) metastatic breast cancers (MBC)." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): 1040. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1040.
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1040 Background: Mutations (mut) in ESR1 have been reported in ER+ breast cancers (BC) as an acquired resistance mut to aromatase inhibitor (AI) therapy. Acquired ERBB2 mut have also been reported in MBC patients (pts) that cause activated ERBB2 signaling. The emergence of acquired secondary mut presents challenges in effective treatment approaches. Methods: Comprehensive genomic profiling was performed on 83 BC samples with 48 metastatic; 34 primary samples. Targeted next-generation sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA (germline) samples. Results: ESR1-mut were found in 23%(11/48) of ER+ MBC tissues with no mut detected in primary ER+ BCs. Mutations-D538G, Y537S and E380Q in the ligand binding domain of ER were the most common alterations, found in 54.5%, 18% and 18% of ESR1 mut samples, respectively. An ER+ HER2- liver biopsy obtained after 20 mos on AI + everolimus had ESR1-D538G and TSC2 structural event. Protein array showed high expression of androgen receptor (AR) and p-AR and activation of ERBB1/2/3, p-SRC and p-4EBP1 in this sample. Further, a functionally uncharacterized ESR1 mut was found in ER+, HER2+ and a triple negative MBC tissue (the primary BC had been ER+). Mut in PI3K pathway (PIK3CA, ARID1A, TSC1/2, PTEN) were present in 8/11 samples with ESR1 mut. Activating mut in ERBB2 were found in 3/83 samples; all 3 were in ER+ MBC samples with one case harboring mut in both ERBB2 and ESR1 (E380Q – uncertain degree of constitutive activity). Interestingly, a BC sample with ER+ HER2- liver met harbored both ERBB2 (V777L) and ERBB3 (E928G) mut; this pt responded well to trastuzumab/pertuzumab (HP) therapy. A pt with ER+ HER2-ERBB2- L755S mut met to gallbladder found after 7 mos on letrozole/palbociclib therapy responded well to HP and T-DM1 therapy. All 3 ERBB2-mut cancers had a CDH1 frameshift mut suggesting enrichment in pretreated lobular MBCs (Ross J. CCR, 2013). Conclusions: This study shows a 23% and 6% ESR1 and ERBB2 mut rate in MBC samples. No ESR1 and ERBB2 mut were present in primary BC samples. Our findings suggest that pts with lobular MBC should be monitored for acquired ERBB2 mut, and that ERBB2 mut may not arise in BCs which harbor known constitutively active ESR1 mut.
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Wang, Peng, Qiaoling Zhang, Lei Han, Yanan Cheng, Zengfeng Sun, Qiang Yin, Zhen Zhang y Jinpu Yu. "Genomic Instability in Cerebrospinal Fluid Cell-Free DNA Predicts Poor Prognosis in Solid Tumor Patients with Meningeal Metastasis". Cancers 14, n.º 20 (14 de octubre de 2022): 5028. http://dx.doi.org/10.3390/cancers14205028.
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Genomic instability (GI), which leads to the accumulation of DNA loss, gain, and rearrangement, is a hallmark of many cancers such as lung cancer, breast cancer, and colon cancer. However, the clinical significance of GI has not been systematically studied in the meningeal metastasis (MM) of solid tumors. Here, we collected both cerebrospinal fluid (CSF) and plasma samples from 56 solid tumor MM patients and isolated cell-free ctDNA to investigate the GI status using a next-generation sequencing-based comprehensive genomic profiling of 543 cancer-related genes. According to the unfiltered heterozygous mutation data-derived GI score, we found that 37 (66.1%) cases of CSF and 3 cases (6%) of plasma had a high GI status, which was further validated by low-depth whole-genome sequencing analysis. It is demonstrated that a high GI status in CSF was associated with poor prognosis, high intracranial pressure, and low Karnofsky performance status scores. More notably, a high GI status was an independent poor prognostic factor of poor MM-free survival and overall survival in lung adenocarcinoma MM patients. Furthermore, high occurrences of the co-mutation of TP53/EGFR, TP53/RB1, TP53/ERBB2, and TP53/KMT2C were found in MM patients with a high GI status. In summary, the GI status in CSF ctDNA might be a valuable prognostic indicator in solid tumor patients with MM.
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Semiglazov, V. F., M. A. Dzhelialova, S. S. Yerechshenko, E. T. Munaeva, R. S. Pesotsky, A. I. Tseluyko, A. S. Emelyanov, R. V. Donskikh y P. V. Krivorotko. "Post-neoadjuvant treatment of breast cancer". Meditsinskiy sovet = Medical Council, n.º 9 (30 de julio de 2020): 232–41. http://dx.doi.org/10.21518/2079-701x-2020-9-232-241.
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Achieving a pathologic complete response as a result of neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial showed a significant survival improvement with capecitabine treatment of patients with residual invasive disease following neoadjuvant chemotherapy, and the KATHERINE trial demonstrated a significant benefit of trastuzumabemtansine (TDM1) in patients with HER2-positive breast cancer who did not achieve a pathologic complete response, so we have a lot of interesting alternatives of post-neoadjuvant treatments for high-risk patients. The discovery of molecular markers of resistance to endocrinotherapy (cyclin-dependent kinases (CDK 4/6), ER mutation (ESR1), mTOR signaling pathway, co-expression of ER+/HER2+) and inhibitors to them expanded the possibilities of endocrinotherapy not only in advanced and metastatic breast cancer, but also in residual ER+ tumors. The pCR rates in hormone receptor-positive breast cancer after neoadjuvant chemotherapy are around 10%, which is much lower than the values observed in HER2-positive and triple negative subtypes, so new strategies are needed to improve pCR rates in this subgroup, even though the adjuvant endocrine therapy impacts significantly the outcomes of this patients. The cyclin-dependent kinases (CDKs) are serine–threonine kinases that regulate cell cycle progression from the G1 to the S-phase during mitosis. CDKs activity can be abnormally increased or dysregulated in breast cancer, leading to a constant stimulus for cell proliferation and survival, which is a known mechanism of resistance to endocrine treatment. The CDK inhibitors act on CDKs and block their activity, thereby restoring the cell cycle regulation. In studies with metastatic hormone receptor-positive breast cancer patients, the combination of a CDKis with first or second-line endocrine therapy showed significant improvements in progression-free survival and response rates. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our understanding of the biology of residual disease and also the mechanisms involved in treatment resistance.
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Bar, Isabelle, Ahmad Merhi, Fadi Abdel-Sater, Abduelhakem Ben Addi, Sara Sollennita, Jean-Luc Canon y Paul Delrée. "The MicroRNA miR-210 Is Expressed by Cancer Cells but Also by the Tumor Microenvironment in Triple-Negative Breast Cancer". Journal of Histochemistry & Cytochemistry 65, n.º 6 (12 de abril de 2017): 335–46. http://dx.doi.org/10.1369/0022155417702849.
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The triple-negative breast cancer (TNBC) subtype occurs in about 15% of breast cancer and is an aggressive subtype of breast cancer with poor outcome. Furthermore, treatment of patients with TNBC is more challenging due to the heterogeneity of the disease and the absence of well-defined molecular targets. Microribonucleic acid (RNA) represents a new class of biomarkers that are frequently dysregulated in cancer. It has been described that the microRNA miR-210 is highly expressed in TNBC, and its overexpression had been linked to poor prognosis. TNBC are often infiltrated by immune cells that play a key role in cancer progression. The techniques traditionally used to analyze miR-210 expression such as next generation sequencing or quantitative real-time polymerase chain reaction (PCR) do not allow the precise identification of the cellular subtype expressing the microRNA. In this study, we have analyzed miR-210 expression by in situ hybridization in TNBC. The miR-210 signal was detected in tumor cells, but also in the tumor microenvironment, in a region positive for the pan-leucocyte marker CD45-LCA. Taken together, our results demonstrate that miR-210 is expressed in tumor cells but also in the tumor microenvironment. Our results also highlight the utility of using complementary approaches to take into account the cellular context of microRNA expression.
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Criscitiello, Carmen, Antonio Marra y Giuseppe Curigliano. "PIK3CA Mutation Assessment in HR+/HER2− Metastatic Breast Cancer: Overview for Oncology Clinical Practice". Journal of Molecular Pathology 2, n.º 1 (11 de marzo de 2021): 42–54. http://dx.doi.org/10.3390/jmp2010005.
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Activation of the PI3K–AKT–mTOR pathway occurs in several human cancers, including hormone receptor (HR)-positive breast cancer (BC) where is associated with resistance to endocrine therapy and disease progression. In BC, the most common PI3K–AKT–mTOR pathway alteration is represented by PIK3CA oncogenic mutations. These mutations can occur throughout several domains of the p110α catalytic subunit, but the majority are found in the helical and kinase domains (exon 9 and 20) that represent the “hotspots”. Considering the central role of the PI3K–AKT–mTOR pathway in HR-positive BC, several inhibitors (both pan-PI3K and isoform-specific) have been developed and tested in clinical trials. Recently, the PI3Kα-selective inhibitor alpelisib was the first PI3K inhibitor approved for clinical use in HR-positive metastatic BC based on the results of the phase III SOLAR-1 trial. Several methods to assess PIK3CA mutational status in tumor samples have been developed and validated, including real-time polymerase chain reaction (PCR), digital droplet PCR (ddPCR), BEAMing assays, Sanger sequencing, and next-generation sequencing (NGS) panels. Several new challenges will be expected once alpelisib is widely available in a clinical setting, including the harmonization of testing procedures for the detection of PI3K–AKT–mTOR pathway alterations. Herein, we provide an overview on PI3K–AKT–mTOR pathway alterations in HR-positive BC, discuss their role in determining prognosis and resistance to endocrine therapy and highlight practical considerations about diagnostic methods for the detection of PI3K–AKT–mTOR pathway activation status.
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Jung, Seung Pil, Soo Youn Bae, Jeong Hyeon Lee y Joung Won Bae. "Differences in prognosis by p53 expression after neoadjuvant chemotherapy in triple-negative breast cancer." Journal of Global Oncology 5, suppl (7 de octubre de 2019): 119. http://dx.doi.org/10.1200/jgo.2019.5.suppl.119.
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119 Background: Triple negative breast cancer (TNBC) exhibits a higher rate of early recurrence and more aggressive behavior. Despite unfavorable prognoses, TNBCs are known to be highly reactive to chemotherapy and show higher pathologic complete response rates after neoadjuvant chemotherapy. However, TNBC patients with residual cancer have significantly worse prognoses than patients with non-TNBC associated residual cancer. TP53 mutations are the most common genetic alterations in breast cancer and are highly linked to basal subtype carcinomas. Past studies have investigated if TP53 mutation can predict the response of cancer to chemotherapy or affect a difference in prognosis; however, the lack of consistent results has hampered clinical applications. Because immunostaining studies can be easily performed, those results may be more useful until Next generation sequencing results are clinically applicable. The aim of this study was to determine whether p53 expression in TNBC could predict the response to neoadjuvant chemotherapy and the resulting prognosis. Methods: From 2009 to 2017, TNBC patients who underwent neoadjuvant chemotherapy were reviewed, including a total of 31 TNBC patients who had clinical lymph node metastasis. The status of p53 expression in patients before and after chemotherapy was evaluated. Results: Two patients (22.2%, 2/9) achieved pCR in p53(+) TNBC and four patients (50%, 5/10) achieved pCR in p53(-) TNBC. There was no correlation between pCR rate and p53 expression ( P= 0.350). Based on pre-chemotherapy p53 expression, there was no significant difference in DFS between p53(+) TNBC and p53(-) TNBC ( P= 0.335) . However, after chemotherapy, p53(+) TNBC had shown higher DFS than p53(-) TBNC ( P= 0.099). Based on pre-chemotherapy p53 expression, p53(+) TNBC had better OS than p53(-) TNBC, but the difference was not statistically significant ( P= 0.082). After chemotherapy, p53(+) TNBC showed significantly better OS than p53(-) TNBC ( P = 0.018). Conclusions: Immunohistochemically detected p53 expression in TNBC could not predict the response to neoadjuvant chemotherapy. However, p53 (+) TNBC had a better OS than p53 (-) TNBC in patients who underwent neoadjuvant chemotherapy.
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Wongchenko, Matthew J., Sung-Bae Kim, Cristina Saura, Mafalda Oliveira, Doron Lipson, Mark Kennedy, Mandy Greene et al. "Circulating Tumor DNA and Biomarker Analyses From the LOTUS Randomized Trial of First-Line Ipatasertib and Paclitaxel for Metastatic Triple-Negative Breast Cancer". JCO Precision Oncology, n.º 4 (septiembre de 2020): 1012–24. http://dx.doi.org/10.1200/po.19.00396.
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PURPOSE Combining the oral AKT inhibitor ipatasertib with paclitaxel as first-line therapy for metastatic triple-negative breast cancer significantly improved progression-free survival (PFS) in the placebo-controlled, randomized, phase II LOTUS trial, with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors. We report findings from the extensive translational research program. PATIENTS AND METHODS Pretreatment plasma and tumor samples were evaluated for genetic alterations using FoundationACT and FoundationOne (Foundation Medicine, Cambridge, MA) hybrid capture next-generation sequencing assays, respectively. Prevalences of the most common mutations and PIK3CA/AKT1 mutation status were determined using both assays, and concordance was assessed. In longitudinal analyses, circulating tumor DNA (ctDNA) mutations were quantified in baseline and on-treatment (cycle 3, day 1 [C3D1]) samples. The relationship between outcomes and ctDNA fraction (CTF; highest variant allele frequency) and CTF ratio (C3D1 CTF to baseline CTF) was explored. RESULTS Among 89 patients evaluable for ctDNA sequencing, 81 patients (91%) had 149 detectable mutations. There was high agreement between plasma- and tissue-based sequencing for known or likely short variant mutations but not amplifications. There was 100% concordance between ctDNA and tissue sequencing in patients with activating PIK3CA or AKT1 mutations. High baseline CTF was associated with shorter PFS in both treatment arms. Longitudinal analyses showed more favorable outcomes with lower absolute CTF at C3D1 and, to a lesser extent, greater CTF decreases. CONCLUSION These results suggest that plasma ctDNA sequencing may allow reliable and convenient assessment of prognosis and identification of genetic markers associated with increased benefit from ipatasertib. On-treatment CTF showed a meaningful association with objective response and PFS.
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Zhou, Li, Maria Rueda y Abedalrhman Alkhateeb. "Classification of Breast Cancer Nottingham Prognostic Index Using High-Dimensional Embedding and Residual Neural Network". Cancers 14, n.º 4 (13 de febrero de 2022): 934. http://dx.doi.org/10.3390/cancers14040934.
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The Nottingham Prognostics Index (NPI) is a prognostics measure that predicts operable primary breast cancer survival. The NPI value is calculated based on the size of the tumor, the number of lymph nodes, and the tumor grade. Next-generation sequencing advancements have led to measuring different biological indicators called multi-omics data. The availability of multi-omics data triggered the challenge of integrating and analyzing these various biological measures to understand the progression of the diseases. High-dimensional embedding techniques are incorporated to present the features in the lower dimension, i.e., in a 2-dimensional map. The dataset consists of three -omics: gene expression, copy number alteration (CNA), and mRNA from 1885 female patients. The model creates a gene similarity network (GSN) map for each omic using t-distributed stochastic neighbor embedding (t-SNE) before being merged into the residual neural network (ResNet) classification model. The aim of this work was to (i) extract multi-omics biomarkers that are associated with the prognosis and prediction of breast cancer survival; and (ii) build a prediction model for multi-class breast cancer NPI classes. We evaluated this model and compared it to different high-dimensional embedding techniques and neural network combinations. The proposed model outperformed the other methods with an accuracy of 98.48%, and the area under the curve (AUC) equals 0.9999. The findings in the literature confirm associations between some of the extracted omics and breast cancer prognosis and survival including CDCA5, IL17RB, MUC2, NOD2 and NXPH4 from the gene expression dataset; MED30, RAD21, EIF3H and EIF3E from the CNA dataset; and CENPA, MACF1, UGT2B7 and SEMA3B from the mRNA dataset.
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Bustos, Matias A., Jun Yin, Pavel Brodskiy, Irene Kang, Stephanie L. Graff, Sarah Sammons, Richa Dawar, David Spetzler y Dave S. B. Hoon. "Association of interleukin-enhanced factor 2 (ILF2) expression with prognosis and clinico-genomic features in breast cancer (BC)." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 1030. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.1030.
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1030 Background: Novel prognostic and predictive biomarkers beyond traditional histological subtypes are needed to better inform outcomes and enhance therapy guidance in breast cancer (BC). We have previously reported that ILF2 was overexpressed in TNBC cell lines and has a functional role in DNA and RNA metabolism, making it a promising biomarker for risk assessment and treatment decisions. Herein, we aim to leverage a large clinico-genomic dataset to further characterize ILF2 in BC patients (pts). Methods: A total of 9456 BC tissue samples underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next generation sequencing of DNA (592 Gene Panel, or Whole Exome Sequencing), and RNA (Whole Transcriptome Sequencing), and immunohistochemistry (IHC). Wilcoxon and Fisher’s exact were used to determine statistical significance. Overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated. Spearman correlation was used to identify highly correlated genes (ρ>0.6) with ILF2 and significant genes that were subsequently analyzed via pathway analysis using STRING. Results: BC pts were grouped into ILF2-High (H, top quartile) and ILF2-Low (L, bottom quartile) based on mRNA expression (TPM). ILF2-H pts were significantly younger (73 vs 80% for pts >50), enriched in ductal histology (90.9 vs 77.7%), TNBC subtype (48.9 vs 18.9%), and had a higher CNS metastases rate (4.3 vs 1.4%) compared to ILF2-L pts (all q<0.0001). ILF2 overexpression was associated with significantly inferior OS in all BC pts (HR 3.38, 95%CI: 2.97 – 3.84); when stratified into known BC hormonal receptor (HR) subtypes, ILF2 was prognostic in both HR+ BC (HR 1.7, 95 CI: 1.34-2.19) and TNBC (HR 3.8, 95 CI: 3.1-4.7), all p<0.0001. In TNBC (n=2468), ILF2-H was associated with a higher frequency of TP53 mutations(mt), lower rate of PIK3CA mt and higher amplification of CCNE1 and FGF23; in HR+/HER2- BC (n = 5071), an association with a higher rate of TP53 mt, PD-L1 expression, NOTCH2 and CCND2 amplification was seen (Table). No significant molecular correlation with ILF2 was seen in HR-/HER2+ BC (n=682). In TNBC, ILF2 expression was significantly correlated with genes involved in spliceosome, cell cycle and RNA transport pathways. In HR+/HER2- BC, ILF2-correlated genes were significantly enriched in mismatch repair and DNA replication pathways (p<0.05 for all factors individually). Conclusions: High expression of ILF2 is associated with a poorer prognosis independent of subtype in BC and our study warrants further investigation on ILF2 as a diagnostic and therapeutic target.[Table: see text]
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Tisman, Glenn. "Cyber Cloud Oncology". Digital Medicine and Health Technology 2022 (25 de agosto de 2022): 1–18. http://dx.doi.org/10.5772/dmht.08.
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Breast cancer treatment is experiencing a groundswell transformation directed by a better understanding of tumour cell metabolism. Observation of metabolic tumor cell variations led to precision medicine. In addition, a “new wave” of rapid drug development spurred by the 2016 U.S. government’s Moonshot program is in the backdrop and, in part, placed an overwhelming burden on clinical oncologists and patients. In 2016, the U.S. government announced the Cancer Moonshot intending to make ten years’ worth of progress in cancer prevention, diagnosis, and treatment in just five years. In the 5-year interval 2017–2021, the FDA issued an unprecedented 161 new approvals of therapeutic agents for various indications in adult patients with solid tumors. Cancer chemotherapy now involves a complex balance between new drug development, clinical trial observations, FDA drug approvals, next-generation sequencing of tumour and blood samples, and “consensus opinion” between medical, surgical, and radiation oncologists. New “precision” medicine selects precise treatment options that benefit patients based on the genomic makeup of their tumour. Genomic profiling provides information about a diagnosis and prognosis and often predicts response or resistance to therapy, years before routine imaging studies change. New technologies, including liquid biopsy and next-generation sequencing (NGS), have identified oncogenic drivers and unique drugs capable of targeting and inhibiting/modifying newly discovered oncogenic driver pathways. Herein is presented a helpful method for keeping track of and rapidly updating physicians on newly developed effective treatments and therapeutic consensus opinion, which often lacks contemporary harmonization between official oncology societies. Physicians and supporting healthcare workers contribute the most to patients when equipped with knowledge of the newest, least toxic, and most effective therapies.
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Hironaka-Mitsuhashi, Ai, Anna Sanchez Calle, Takahiro Ochiya, Shin Takayama y Akihiko Suto. "Towards Circulating-Tumor DNA-Based Precision Medicine". Journal of Clinical Medicine 8, n.º 9 (2 de septiembre de 2019): 1365. http://dx.doi.org/10.3390/jcm8091365.
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In the era of precision medicine, targeted therapies have been implemented for various diseases. Genomic information guides decision-making in cancer treatment. The improvements in next-generation sequencing and polymerase chain reaction have made it possible to access the genetic information using circulating-tumor DNAs (ctDNAs). Molecular characteristics of individual tumors can be obtained by analysis of ctDNAs, thus making them excellent tools to guide decision-making during treatment. In oncology, the use of ctDNAs in clinical practice is now gaining importance. Molecular analysis of ctDNAs has potential for multiple clinical applications, including early diagnosis, prognosis of disease, prognostic and/or predictive biomarkers, and monitoring response to therapy and clonal evolution. In this paper, we highlight the applications of ctDNAs in cancer management, especially in metastatic setting, and summarize recent studies about the use of ctDNAs as predictive biomarkers for the therapeutic adaptation/response in lung cancer, breast cancer, and colorectal cancer. These studies offer the evidence to use ctDNAs as a promising approach to solve unmet clinical needs.
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Dackus, Gwen MHE, Natalie D. ter Hoeve, Mark Opdam, Willem Vreuls, Zsuzsanna Varga, Esther Koop, Stefan M. Willems et al. "Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study". BMJ Open 7, n.º 11 (noviembre de 2017): e017842. http://dx.doi.org/10.1136/bmjopen-2017-017842.
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IntroductionCurrently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient’s prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged≤40 years.Methods and analysisAll young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle.Ethics and disseminationObservational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a ‘non-WMO’ declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.
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McDonnell, Kevin, Amit Kulkarni, Melissa Woodhouse, Sidney A. Smith, Christine Hong, Marilena Melas, Kathleen Heller et al. "Advancing precision medicine in clinical oncology: Whole exome paired tumor-normal DNA and RNA sequencing at a single-institution cancer center." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e14006-e14006. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14006.
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e14006 Background: Next generation sequencing (NGS) allows for reliable, comprehensive and cost-effective identification of clinically actionable genetic and genomic alterations. The increasing adoption of NGS in clinical oncology has increased our ability to identify germline alterations predisposing to cancer development as well as somatic changes enabling prescription of individualized cancer treatment and enhanced clinical trial participation. Here we summarize implementation of an NGS-based precision medicine initiative involving oncology patients from a single institution cancer center. Methods: IRB-approved NGS matched whole exome (WES) germline and solid tumor somatic tumor sequencing together with somatic tumor RNA sequencing (RNA-seq) were performed using germline DNA extracted from peripheral blood lymphocytes and nucleic acids for tumor DNA and RNA sequencing obtained from formalin-fixed, paraffin-embedded tumor specimens. Results of sequencing and analyses were presented to a multi-disciplinary tumor board to establish recommendations for management of germline pathogenic variation, therapeutic drug matching, clinical trials eligibility and molecularly informed patient prognosis. Results: A total of 1,005 patients completed sequencing. Germline and somatic WES exceeded 100X and 250X mean target coverage, respectively; somatic RNA-seq exceeded 200 million mean reads. Patients ranged in age from 17 to 90 years. The study cohort comprised comparable numbers of female (51%) and male (49%) patients. Ethnicities and races were broadly represented with 22% of participants identifying as Hispanic, 14% as Asian, 4% as Black, 55% as Non-Hispanic White and 5% as other. The most common solid tumor histological classification was colorectal (18%), followed by breast (16%), prostate (7%), head and neck (7%), sarcoma (7%), ovarian (5%), melanoma (4%) and lung (3%). Bioinformatic analyses and precision medicine tumor board review established that 12% of patients harbored a germline pathogenic variant and 43% carried clinically actionable genetic/genomic alterations; a majority of patients met molecular requirements for participation in a clinical trial. Conclusions: This study confirms the feasibility and utility of clinical NGS and precision medicine tumor board review in clinical oncology to identify germline genetic pathology, deliver personalized cancer therapeutics, increase clinical trial enrollment and clarify diagnosis and prognosis.
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Liegmann, Anna-Sophie, Kerstin Heselmeyer-Haddad, Annette Lischka, Daniela Hirsch, Wei-Dong Chen, Irianna Torres, Timo Gemoll et al. "Single Cell Genetic Profiling of Tumors of Breast Cancer Patients Aged 50 Years and Older Reveals Enormous Intratumor Heterogeneity Independent of Individual Prognosis". Cancers 13, n.º 13 (5 de julio de 2021): 3366. http://dx.doi.org/10.3390/cancers13133366.
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Purpose: Older breast cancer patients are underrepresented in cancer research even though the majority (81.4%) of women dying of breast cancer are 55 years and older. Here we study a common phenomenon observed in breast cancer which is a large inter- and intratumor heterogeneity; this poses a tremendous clinical challenge, for example with respect to treatment stratification. To further elucidate genomic instability and tumor heterogeneity in older patients, we analyzed the genetic aberration profiles of 39 breast cancer patients aged 50 years and older (median 67 years) with either short (median 2.4 years) or long survival (median 19 years). The analysis was based on copy number enumeration of eight breast cancer-associated genes using multiplex interphase fluorescence in situ hybridization (miFISH) of single cells, and by targeted next-generation sequencing of 563 cancer-related genes. Results: We detected enormous inter- and intratumor heterogeneity, yet maintenance of common cancer gene mutations and breast cancer specific chromosomal gains and losses. The gain of COX2 was most common (72%), followed by MYC (69%); losses were most prevalent for CDH1 (74%) and TP53 (69%). The degree of intratumor heterogeneity did not correlate with disease outcome. Comparing the miFISH results of diploid with aneuploid tumor samples significant differences were found: aneuploid tumors showed significantly higher average signal numbers, copy number alterations (CNAs) and instability indices. Mutations in PIKC3A were mostly restricted to luminal A tumors. Furthermore, a significant co-occurrence of CNAs of DBC2/MYC, HER2/DBC2 and HER2/TP53 and mutual exclusivity of CNAs of HER2 and PIK3CA mutations and CNAs of CCND1 and PIK3CA mutations were revealed. Conclusion: Our results provide a comprehensive picture of genome instability profiles with a large variety of inter- and intratumor heterogeneity in breast cancer patients aged 50 years and older. In most cases, the distribution of chromosomal aneuploidies was consistent with previous results; however, striking exceptions, such as tumors driven by exclusive loss of chromosomes, were identified.
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Premji, Sarah, Valentina Hoyos, Shaun Bulsara, Susan G. Hilsenbeck, Maryam Nemati Shafaee, Matthew James Ellis, C. Kent Osborne, Mothaffar F. Rimawi y Julie R. Nangia. "Change in management based on actionable mutations in metastatic breast cancer in an ethnically diverse cohort: Single institution experience." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): e13067-e13067. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13067.
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e13067 Background: Recently, next generation sequencing (NGS) has been used with increasing frequency to guide therapy decisions for patients with metastatic solid tumors. NGS is a DNA sequencing technology that detects somatically acquired mutations. If an actionable mutation is identified, it may affect prognosis and guide therapy. At our institution we serve a large proportion of minority and underserved patients and analyzed their NGS results to determine if there was a change in management. Methods: Patients with metastatic breast cancer treated at one of two sites at Baylor College of Medicine who underwent NGS via Tempus between 2018-2020 were included. Tempus provided access to the variant database for these patients. We analyzed the charts of 43 patients who underwent NGS via Tempus on tissue, blood or both. In those patients with clinically actionable mutations, we noted if there was a change in management. Utilizing Redcap, we extracted demographics, sites of metastasis, biomarker activity and site, genomic sequencing, and duration and sequencing of therapies given along with clinical trial information. Results: Of the 43 patients included in this analysis, the mean age was 55 years, 33% were African American, 30% were Hispanic, 21% were white/non-Hispanic, 12% were Asian, 4% were other. Two thirds of patients were treated in the Harris Health System (a safety net hospital with a unique and diverse population) while one third was treated at the Baylor St. Luke’s Medical Center (a private academically affiliated institution). Of the 43 patients, 14 had PIK3CA mutations and 3 had a change in management. 2 patients had microsatellite instability (MSI) and received immunotherapy, and 1 patient had a HER2 mutation and entered a clinical trial with Neratinib. Additionally, 2 patients were incidentally found to have MUTYH germline mutation which is associated with polyposis. Conclusions: With increasing frequency, patients with metastatic malignancy undergo NGS in order to determine if there is an actionable mutation that can guide their next line of treatment. However, this technology could be cost prohibitive for many underserved patients. Our study analyzes a unique and diverse population of patients, many of whom are underserved. We were able conduct this testing in our cohort, study the frequency of somatic mutations and monitor for change in treatment. Of the variants analyzed, PIK3CA mutations are actionable and patients can receive Alpelisib + Fulvestrant- however many did not. There was not a large shift in management based on the incorporation of this DNA sequencing technology which suggests that, unlike the case of other solid tumors, there aren’t yet as many actionable targets for patients with metastatic breast cancer. Shared decision making along with consideration of cost is paramount for these patients as we shift into an era of highly personalized medicine.