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Pospíšková, Markéta, and Milan Kohoutek. "Breast cancer a chronic disease? The Anti-HER2 therapy." Klinická farmakologie a farmacie 30, no. 4 (December 1, 2016): 28–30. http://dx.doi.org/10.36290/far.2016.032.
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Nahleh, Zeina A., Elizabeth B. Elimimian, Leah C. Elson, Brian Hobbs, Wei Wei, and Cassann N. Blake. "Endocrine Therapy Plus Anti-HER2 Therapy as Adjuvant Systemic Therapy for Luminal HER2-Positive Breast Cancer: An Analysis of the National Cancer Database." Breast Cancer: Basic and Clinical Research 14 (January 2020): 117822342094569. http://dx.doi.org/10.1177/1178223420945694.
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Background: Guidelines regarding the usage of adjuvant systemic therapy in patients with small human epidermal growth factor receptor 2 (HER2)-positive and estrogen receptor/progesterone receptor–positive (luminal HER2 positive) tumors are nonspecific. Outcomes of chemotherapy followed by endocrine therapy (ET), with or without anti-HER2 therapy, vs ET alone (no chemotherapy) have not been widely studied in this disease subtype. We sought to examine the usage and outcomes of adjuvant systemic therapy (ET vs chemotherapy with or without trastuzumab) in stage I luminal HER2-positive breast cancer (BC), based on the large National Cancer Database. Methods: We conducted a retrospective analysis of patients with luminal HER2-positive stage I BC, diagnosed between 2010 and 2015, in the United States, using univariable and multivariable logistic regression analyses. The Kaplan-Meier method estimated overall survival (OS). Results: A total of 37 777 patients were included in the analysis; of these, n = 32 594 (86%) received adjuvant ET and n = 5183 (14%) received chemotherapy. Around 40% of all patients received anti-HER2 therapy (trastuzumab). Patients who received trastuzumab had a better 5-year OS (93.4% vs 92.0%, P = .0002) compared with those who did not. Patients who received anti-HER2 therapy plus ET had the best OS rate at 5 years (93.5%, confidence interval [CI]: 89.2%-98%, P < .0001) compared with those receiving anti-HER2 therapy plus chemotherapy (92.7%, CI: 89.4%-96.1%, P < .0001). Conclusions: Most patients in the United States, with stage I luminal HER2 positive BC, received ET, not chemotherapy but most of them do not receive anti-HER2 therapy resulting in inferior outcome. Future trials exploring the de-escalation of systemic adjuvant therapy for early-stage luminal HER2-positive BC to ET plus anti-HER2 therapy would be desirable.
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Babar, Tania, Christopher Blomberg, Eileen Hoffner, and Xinhua Yan. "Anti-HER2 Cancer Therapy and Cardiotoxicity." Current Pharmaceutical Design 20, no. 30 (August 31, 2014): 4911–19. http://dx.doi.org/10.2174/1381612820666140604145037.
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Lück, Hans-Joachim, Michael Untch, Christian Jackisch, Christoph Zielinski, and Rupert Bartsch. "Optimal Sequencing of Anti-HER2 Therapy." Breast Care 9, no. 2 (2014): 138. http://dx.doi.org/10.1159/000362300.
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Martínez-Jañez, Noelia, Ignacio Chacón, Ana de Juan, Luis Cruz-Merino, Sònia del Barco, Isaura Fernández, Paula García-Teijido, et al. "Anti-HER2 Therapy Beyond Second-Line for HER2- Positive Metastatic Breast Cancer: A Short Review and Recommendations for Several Clinical Scenarios from a Spanish Expert Panel." Breast Care 11, no. 2 (2016): 133–38. http://dx.doi.org/10.1159/000443601.
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Background: The aim of this project was to provide an expert opinion regarding anti-human epidermal growth factor receptor 2 (HER2) therapy beyond second-line treatment of metastatic breast cancer (mBC). Methods: A group of experts discussed specific issues concerning anti-HER2 therapy in late-line settings in mBC. Results: Trastuzumab emtansine (T-DM1) or dual HER2 blockade appeared to be good options for HER2-positive mBC after ≥ 2 HER2-targeted therapies. Once an objective response has been achieved with anti-HER2-containing therapy, the anti-HER2 agent can be continued until progression of the disease, unacceptable toxicity or patient decision. mBC treated with ≥ 3 consecutive lines of anti-HER therapy, ≥ 1 being a dual HER2 blockade and with early progression of disease during a fourth or later-line treatment, are clinically resistant to anti-HER therapy. For progression of metastasis in the brain after anti-HER2 therapy, lapatinib and chemotherapy appear to be a good alternative after best local treatment. Conclusions: Further clinical trials are needed to provide valuable knowledge about the best treatment options in the later settings of mBC.
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Crespo, James, Hongxia Sun, Jimin Wu, Qingqing Ding, Guilin Tang, Melissa Robinson, Hui Chen, Aysegul A. Sahin, and Bora Lim. "HER2 targeted therapy and outcome in HER2-equivocal cases after 2018 ASCO/CAP HER2 guideline modification." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14729-e14729. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14729.
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e14729 Background: The best targeted therapeutic approach for HER2-equivocal cases remains unclear. New ASCO/CAP HER2 guidelines are intended to decrease this ambiguity by combining immunohistochemistry and in situ hybridization to resolve equivocal cases as positive or negative. However, the benefit of anti-HER2 therapy in HER2-equivocal cases is unknown. Methods: We retrospectively reviewed patients who visited MD Anderson from April 2017 to March 2018 with equivocal HER2 results based on the 2013 ASCO/CAP guidelines. The population was divided into 2 cohorts according to biopsy origin (primary cohort: biopsy from breast or axilla; recurrent/metastatic cohort: biopsy from recurrent or metastatic site). HER2 status was redefined using the 2018 ASCO/CAP guidelines. OS and PFS were calculated (Kaplan-Meier method) based on redefined HER2 status and use of HER2 targeted therapy. Results: A total of 139 equivocal results were found. Primary cohort had 90 patients (33 received neoadjuvant and 57 adjuvant therapy). HER2 IHC results were 0 (6.6%), 1+ (37.7%), 2+ (50%), 3+ (1.1%), and no IHC (4.4%). 94% of HER2-equivocal results became HER2 negative. Only 5 patients received anti-HER2 therapy, all of them in the HER2-negative group. After median follow-up of 1.91 yrs, 3 deaths and 8 progressions had occurred. There was no statistically significant association between anti-HER2 therapy and OS (p = 0.67) or PFS (p = 0.49). The recurrence/metastatic cohort had 49 cases with equivocal results. HER2 IHC results were 0 (6.1%), 1+ (22.4%), 2+ (26.5%), and no IHC (44.9%). 55% of HER2-equivocal results became HER2 negative, and only 1 patient received anti-HER2 therapy. After median follow-up of 2.96 yrs, 15 deaths and 35 progressions had occurred. There was no statistically significant association between anti-HER2 therapy and OS (p = 0.61) or PFS (p = 0.78). Conclusions: Most HER2-equivocal results were redefined as HER2 negative using the new ASCO/CAP guidelines. Association between anti-HER2 therapy and OS or PFS according to the new HER2 status was not observed. Although this is a small sample with short follow-up, patients with HER2-equivocal breast cancers seem to have clinical behavior similar to HER2-negative breast cancer.
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Mehta, Sandhya, Jinlin Song, Melissa Pavilack, Jipan Xie, Xiaoyu Nie, Mohini Vembusubramanian, and Jackie Kwong. "Utilization of anti-HER2 regimens among HER2-positive metastatic breast cancer patients." Journal of Clinical Oncology 38, no. 29_suppl (October 10, 2020): 282. http://dx.doi.org/10.1200/jco.2020.38.29_suppl.282.
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282 Background: HER2-positive (+) metastatic breast cancer (mBC) has a poor prognosis and many patients require multiple lines of HER2 targeted regimens. This study aims to examine the treatment sequencing of anti-HER2 regimens for HER2+ mBC among Medicare beneficiaries. Methods: A retrospective study was conducted using linked 1999-2016 Surveillance, Epidemiology, and End Results (SEER) cancer registries and Medicare claims. Adults patients who had mBC diagnosis, HER2+ status documented in SEER or claims of ≥1 anti-HER2 drug, continuous enrollment in Medicare from the date of mBC diagnosis until end of study period/death, and 2 anti-HER2 regimens with or without chemotherapy (Ch) or hormonal therapy (HT) were included. Discontinuation of anti-HER2 regimen was defined as the absence of claims for all anti-HER2 drugs for >60 days, or initiation of a different anti-HER2 drug. Re-initiation of the same regimen after >60 days was considered as a new regimen. The first two anti-HER2 regimens and subsequent therapies were summarized. Results: 804 patients with 2 anti-HER2 regimens were included. Trastuzumab (T) based regimen (defined as: T±Ch/HT; without other anti-HER2 drugs) was the most common 1st regimen (82%), followed by T+ pertuzumab (P) (14%) and lapatinib (L) (3%). For the 2nd regimen, T (52%) was most common, followed by T+P (18%), L (11%), trastuzumab emtansine (T-DM1) (11%) and T+L (7%). After a 2nd regimen, 578 (72%) initiated a subsequent therapy, with over half switching to non-targeted therapies [52%; HT alone (35%), Ch±HT (17%)] followed by T (17%), T-DM1 (12%) and T+P (7%). Among those with subsequent therapy, 2 T-based regimens followed by HT alone (21%) was the most common sequence. After the 1st regimen, 52% patients reused the same anti-HER2 drugs in the 2nd regimen, 21% added another anti-HER2 drug and 27% switched to a different anti-HER2 regimen. After the 2nd regimen, 14% reused anti-HER2 drugs and 6% added another anti-HER2 drug, 25% switched to a different anti-HER2 regimen; 15% reused anti-HER2 drugs from the 1st regimen. Conclusions: Trastuzumab based regimen was the mainstay of anti-HER2 drug regimens during the study timeframe. Despite availability of multiple anti-HER2 drugs, reuse of prior anti-HER2 drugs and switching to non-targeted therapies alone were common after using 2 anti-HER2 regimens. These findings underscore the unmet needs in later lines of therapy. Recently approved anti-HER2 agents may provide additional treatment options for pre-treated HER2+ metastatic breast cancer patients.
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Katayama, Ayaka, Islam M. Miligy, Sho Shiino, Michael S. Toss, Karim Eldib, Sasagu Kurozumi, Cecily M. Quinn, et al. "Predictors of pathological complete response to neoadjuvant treatment and changes to post-neoadjuvant HER2 status in HER2-positive invasive breast cancer." Modern Pathology 34, no. 7 (February 1, 2021): 1271–81. http://dx.doi.org/10.1038/s41379-021-00738-5.
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AbstractThe response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.
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Petráková, Katarína. "Residual disease after neoadjuvant systemic anti-HER2 therapy: the KATHERINE trial." Onkologie 14, no. 2 (June 2, 2020): 93–95. http://dx.doi.org/10.36290/xon.2020.017.
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Raghav, Kanwal, Jonathan M. Loree, Jeffrey S. Morris, Michael J. Overman, Ruoxi Yu, Funda Meric-Bernstam, David Menter, et al. "Validation of HER2 Amplification as a Predictive Biomarker for Anti–Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer." JCO Precision Oncology, no. 3 (December 2019): 1–13. http://dx.doi.org/10.1200/po.18.00226.
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Purpose HER2 amplification has been implicated in resistance to therapy with anti–epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of HER2 amplification in mCRC. Patients and Methods We analyzed patients with RAS/BRAF wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), HER2 amplification was tested in tumor tissue using dual in situ hybridization ( HER2 amplification: HER2/CEP17 ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with HER2 amplification and 54 HER2 nonamplified controls identified by next-generation sequencing ( HER2 amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test. Results Median PFS in cohort 1 on anti-EGFRab–based therapy was significantly shorter in patients with HER2 amplification compared with HER2 nonamplified patients (2.8 v 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; P < .001). These findings were validated in cohort 2 (median PFS for HER2 amplified v nonamplified: 2.8 v 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; P < .001). The median PFS on therapy without anti-EGFRabs was similar among HER2-amplified and nonamplified patients in both cohort 1 (9.7 v 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; P = .97) and cohort 2 (9.6 v 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; P = .66). In multivariable analyses, HER2 amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; P < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; P < .001). Conclusion HER2 amplification in RAS/RAF wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with RAS/BRAF wild-type mCRC for HER2 amplification should be considered before anti-EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.
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von Minckwitz, G. "138 Anti-HER2 therapy treatment after progression." European Journal of Cancer Supplements 7, no. 2 (September 2009): 34–35. http://dx.doi.org/10.1016/s1359-6349(09)70121-1.
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Killock, David. "Leveraging ADCC to enhance anti-HER2 therapy." Nature Reviews Clinical Oncology 14, no. 4 (February 14, 2017): 200. http://dx.doi.org/10.1038/nrclinonc.2017.19.
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Iwata, Hiroji. "The perspective of anti-HER2 therapy for HER2 positive breast cancer." Annals of Oncology 26 (November 2015): vii11. http://dx.doi.org/10.1093/annonc/mdv405.03.
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Oke, Oluchi, Carla L. Warneke, Mariana Chavez-Mac Gregor, Andrea Milbourne, and Jennifer Keating Litton. "Outcomes related to delayed initiation of anti-HER 2 therapy in pregnant HER2 positive breast cancer patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e12059-e12059. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12059.
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e12059 Background: Overexpression of HER2 is associated with aggressive breast cancers. In non-pregnant HER2+ breast cancer patients, anti-HER2 therapy is usually initiated after surgery or in the neoadjuvant setting. However, for pregnant HER2+ breast cancer patients, anti-HER2 therapy must be delayed until after delivery due to fetal toxicity. We describe here the outcomes of pregnant patients with HER2+ breast cancer at a single center. Methods: Twenty-three pregnant HER2+ breast cancer patients were treated between November 1989 to October 2016. Median age at diagnosis was 31.8. (Table 1) We report Kaplan-Meier estimates of OS from diagnosis and PFS from surgery. The effect of time from diagnosis to anti-HER2 therapy (TTH) on OS and PFS from HER2 therapy initiation was assessed using Cox proportional hazards regression models. Results: Seventeen patients received anti-HER2 therapy after delivery, 6 did not – 4 were treated prior to the use of HER2 therapies, and 2 were lost to follow-up. Median TTH was 181 days. All but 3 patients started HER2 treatment within 2 months of delivery. Twenty-one received anthracycline-based chemotherapy during pregnancy. Three patients have died, with all 3 receiving HER2 therapy, but one only at relapse due to diagnosis before routine trastuzumab use. Median follow-up was 3.4 years (range 0.2-16.2 years), and 5-year OS was 80% (95%CI 41-95%). Five patients progressed. Median PFS was 3.1 years (range 0.3-14.2 years), and 5-year PFS was 75% (95%CI 46-90%). Delay of initiation of HER-2 therapy did not appear to be associated with OS or PFS from date of HER-2 therapy initiation (both n = 17, HR 1.01, 95%CI 0.97-1.06, P= 0.52). Conclusions: In this small case series, we did not detect adverse outcomes associated with delaying initiation of anti-HER2 therapy in pregnant patients with HER2+ breast cancer. Larger series are needed to further evaluate this concern. [Table: see text]
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Chia, Stephen K. "Neoadjuvant and Adjuvant Therapy for HER2 Positive Disease." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): e41-e48. http://dx.doi.org/10.14694/edbook_am.2015.35.e41.
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Since the initial description of the HER2 proto-oncogene as a poor prognostic factor in breast cancer in 1987, to the first randomized trial of a monoclonal antibody directed against HER2 in combination with chemotherapy for the treatment of metastatic HER2-positive breast cancer published in 2001, to the American Society of Clinical Oncology (ASCO) 2005 Annual Meeting in which we saw the unprecedented collective presentations demonstrating the dramatic benefit of trastuzumab in the adjuvant setting—the clinical landscape of HER2-overexpressing breast cancer has forever changed. More recently, there has been increasing use of preoperative chemotherapy and anti-HER2 targeted therapies in primary operable HER2 disease in the research domain and in clinical practice. In the next few years, we will see if dual adjuvant anti-HER2 antibody inhibition produces clinically significant improvements in outcome; understand if there is a role of small molecule inhibitors of the HER family of receptors either in combination or sequential to trastuzumab; further refine the relationship between pathologic complete response (pCR) and long-term clinical outcomes; and find predictive biomarkers to identify cohorts of patients that may need differential combinations and/or durations of anti-HER2 therapies.
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Pernas, Sonia, and Sara M. Tolaney. "HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance." Therapeutic Advances in Medical Oncology 11 (January 2019): 175883591983351. http://dx.doi.org/10.1177/1758835919833519.
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The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.
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Bick, Gregory, Jasmine Zhang, Elyse E. Lowe, and Xiaoting Zhang. "Transcriptional coactivator MED1 in the interface of anti-estrogen and anti-HER2 therapeutic resistance." Cancer Drug Resistance 5, no. 2 (2022): 498–510. http://dx.doi.org/10.20517/cdr.2022.33.
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Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide. About 90% of breast cancers belong to ER+ or HER2+ subtypes and are driven by key breast cancer genes Estrogen Receptor and HER2, respectively. Despite the advances in anti-estrogen (endocrine) and anti-HER2 therapies for the treatment of these breast cancer subtypes, unwanted side effects, frequent recurrence and resistance to these treatments remain major clinical challenges. Recent studies have identified ER coactivator MED1 as a key mediator of ER functions and anti-estrogen treatment resistance. Interestingly, MED1 is also coamplified with HER2 and activated by the HER2 signaling cascade, and plays critical roles in HER2-mediated tumorigenesis and response to anti-HER2 treatment as well. Thus, MED1 represents a novel crosstalk point of the HER2 and ER pathways and a highly promising new therapeutic target for ER+ and HER2+ breast cancer treatment. In this review, we will discuss the recent progress on the role of this key ER/HER2 downstream effector MED1 in breast cancer therapy resistance and our development of an innovative RNA nanotechnology-based approach to target MED1 for potential future breast cancer therapy to overcome treatment resistance.
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Kamada, Yoshihiko, Naoko Takigami, Kanou Uehara, Kentaro Tamaki, and Nobumitsu Tamaki. "Survival of stage 4 primary breast cancer cases after surgery by intrinsic subtype: HER2-positive subtype potentially curable." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e13026-e13026. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e13026.
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e13026 Background: With the incorporation of anti-HER2 agents in the treatment of HER2 positive primary breast cancer, stage 4 disease of this subtype has become potentially curable. However, the duration of clinical CR that is needed be certain that the patient is cured, and therefore the necessary duration of anti-HER2 treatment is uncertain. We address this issue in this presentation. Methods: We present cases of stage 4 primary breast cancer who underwent breast surgery after their distant metastases were controlled, with continued post-operative systemic therapy. There were 52 cases of which the intrinsic subtype as of immunohistochemical analysis was as follows; Luminal A - 7 cases, Luminal B, - 14 cases, Luminal-HER2 - 9 cases, HER2-enriched - 7 cases, and Triple negative -15 cases. The patients were followed up for duration of treatment and overall survival. Results: The average post-operative observation period for all 52 cases was 32.6 months. The five year overall survival rate for HER2-enriched cases was 100%, for Luminal-HER2 cases 80%, for Luminal A cases 80%, for Luminal B cases 55%, and for Triple-negative cases 0%. Of the 16 HER2 positive cases (Luminal-HER2 and HER2 enriched), there was only one death at 48.4 months post-operation. The survival of 5 of 15 surviving HER2 positive cases exceed 60 months (5 years). Of the five, only one at 72.0 months has clinically observable disease (cSD). The remaining 4 cases all are clinically disease free (cCR). Of the 4 cCR cases, only 1 case which originally had multiple lung metastases is continuing anti-HER2 therapy at 90.3 months post-operation. The remaining three discontinued anti-HER2 therapy at 18.1 months (lung metastases CR, observation period 71.7 months), 72.3 months (liver and lymph node metastases CR, observation period 90.3 months), and 101.9 months (liver and bone metastases CR, observation period 102.3 months), respectively. The last case terminated anti-HER2 therapy after testing negative for ERBB2 related genes on liquid biopsy. Conclusions: With the proper incorporation of anti-HER2 therapy, Stage 4 HER2 positive primary breast cancer disease seems to be a potentially curable disease, and anti-HER2 therapy probably can be discontinued in cCR patients after 5 years. Liquid biopsy for tumor related genes (e.g. ctDNA, miRNA) might facilitate decision making.
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Ramamoorthi, Ganesan, Krithika Kodumudi, Colin Snyder, Payal Grover, Hongtao Zhang, Mark I. Greene, Amrita Basu, et al. "Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma." Journal for ImmunoTherapy of Cancer 10, no. 6 (June 2022): e004841. http://dx.doi.org/10.1136/jitc-2022-004841.
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BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor.MethodsBALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot.ResultsHER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75–80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways.ConclusionsHER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.
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Crespo, James, Hongxia Sun, Jimin Wu, Qing-Qing Ding, Guilin Tang, Melissa K. Robinson, Hui Chen, Aysegul A. Sahin, and Bora Lim. "Rate of reclassification of HER2-equivocal breast cancer cases to HER2-negative per the 2018 ASCO/CAP guidelines and response of HER2-equivocal cases to anti-HER2 therapy." PLOS ONE 15, no. 11 (November 12, 2020): e0241775. http://dx.doi.org/10.1371/journal.pone.0241775.
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Purpose The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline on HER2 testing in breast cancer permits reclassification of cases with HER2-equivocal results by FISH. The impact of such reclassification is unclear. We sought to determine the proportion of HER2-equivocal cases that are reclassified as HER2-negative and the impact of anti-HER2 therapy on survival in HER2-equivocal cases. Methods We reviewed medical records of breast cancer patients who had HER2 testing by fluorescence in stitu hybridization (FISH) and immunohistochemistry (IHC) performed or verified at The University of Texas MD Anderson Cancer Center during April 2014 through March 2018 and had equivocal results according to the 2013 ASCO/CAP guideline. The population was divided into 2 cohorts according to whether the biopsy specimen analyzed came from primary or from recurrent or metastatic disease. HER2 status was reclassified according to the 2018 ASCO/CAP guideline. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method, and the relationship between anti-HER2 therapy and clinical outcomes was assessed. Results We identified 139 cases with HER2-equivocal results according to the 2013 ASCO/CAP guideline: 90 cases of primary disease and 49 cases of recurrent/metastatic disease. Per the 2018 ASCO/CAP guideline, these cases were classified as follows: overall, HER2-negative 112 cases (80%), HER2-positive 1 (1%), and unknown 26 (19%); primary cohort, HER2-negative 85 (94%), HER2-positive 1 (1%), unknown 4 (4%); and recurrent/metastatic, HER2-negative 27 (55%) and unknown 22 (45%). Five patients in the primary-disease cohort and 1 patient in the recurrent/metastatic-disease cohort received anti-HER2 therapy. There was no significant association between anti-HER2 therapy and OS or EFS in either cohort (primary disease: OS, p = 0.67; EFS, p = 0.49; recurrent/metastatic-disease, OS, p = 0.61; EFS, p = 0.78. Conclusions The majority of HER2-equivocal breast cancer cases were reclassified as HER2-negative per the 2018 ASCO/CAP guideline. No association between anti-HER2 therapy and OS or EFS was observed. HER2-equivocal cases seem to have clinical behavior similar to that of HER2-negative breast cancers.
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Loft, Matthew, Sheau Wen Lok, Richard H. De Boer, Laeeq Malik, Sally Greenberg, Belinda Yeo, Angelyn Anton, et al. "Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1038. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1038.
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1038 Background: The combination of dual anti-HER2 targeted therapy and chemotherapy is the current first line standard of care for HER2+ metastatic breast cancer. Endocrine therapy (ET) is the backbone of treatment in hormone receptor positive (HR+) disease, but the role of the addition of endocrine therapy following chemotherapy in HER2+/HR+ disease remains unclear as pivotal first line clinical trials excluded endocrine therapy use. Methods: Data from a multi-site community cohort of consecutive HER2+ metastatic breast cancer patients diagnosed between 1 January 2012 and 31 August 2019 was examined. Patients were treated at clinician discretion. The subset of patients eligible for this analysis were those that were HR+ and had received first line dual anti-HER2 targeted therapy. Results: Of 132 eligible patients included in the analysis, 78 (59.1%) received endocrine therapy and 54 (40.9%) did not. Median follow up was 25.9 months. There were no significant differences between the two groups based on age, performance status, previous therapy or de novo disease (Table), however, patients with bone metastases were more likely to receive ET in conjunction with first line dual anti-HER2 therapy (71% vs 52%, p= .043). The addition of ET was associated with improved progression free (HR 2.1, 95% CI 1.2-3.5, p = 0.007) and overall survival (HR 2.7, 95% CI 1.2-5.5, p = 0.007) in multivariate analysis. No increase in serious adverse events was noted although endocrine therapy related toxicities were not specifically collected. Conclusions: In this real-world series, the addition of ET to first line dual anti-HER2 therapy in HER2+/HR+ metastatic breast cancer was associated with improved progression free and overall survival. Further research is required to validate these findings and examine the role of CDK4/6 inhibitors in this disease, but may provide reassurance to clinicians considering ET in this clinical context. [Table: see text]
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Mahdi, H., M. Hasipek, Y. Guan, D. Grabowski, H. Q. Al-Sudani, Y. Parker, A. Boyd, P. G. Rose, D. Lindner, and B. K. Jha. "Dual anti-HER2 therapy in HER2+ uterine and ovarian carcinomas: Durable effect with combined therapy." Gynecologic Oncology 154 (June 2019): 85–86. http://dx.doi.org/10.1016/j.ygyno.2019.04.201.
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Advani, Pooja P., Jennifer A. Crozier, and Edith A. Perez. "HER2 testing and its predictive utility in anti-HER2 breast cancer therapy." Biomarkers in Medicine 9, no. 1 (January 2015): 35–49. http://dx.doi.org/10.2217/bmm.14.95.
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MacNeil, Ian A., David J. Burns, Benjamin E. Rich, Sajjad M. Soltani, Samantha Kharbush, Nicole G. Osterhaus, Brian F. Sullivan, Douglas M. Hawkins, Jodie R. Pietruska, and Lance G. Laing. "New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified." Journal of Cancer Research and Clinical Oncology 146, no. 3 (February 8, 2020): 605–19. http://dx.doi.org/10.1007/s00432-020-03144-7.
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Gaibar, Maria, Laura Beltrán, Alicia Romero-Lorca, Ana Fernández-Santander, and Apolonia Novillo. "Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer." Journal of Oncology 2020 (March 7, 2020): 1–13. http://dx.doi.org/10.1155/2020/6375956.
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In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.
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Kolyadina, I. V., and I. V. Poddubnaya. "Key studies that have changed the history and treatment of early HER2+ breast cancer: focus on individual therapy." Tumors of female reproductive system 16, no. 3 (January 12, 2021): 46–56. http://dx.doi.org/10.17650/1994-4098-2020-16-3-46-55.
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HER2-positive breast cancer is a unique subtype of the disease, not only in terms of aggressive biology, but also in terms of treatment options. Over the past 15 years, the strategy for treating early HER2-positive breast cancer has undergone a real evolution – from the absence of anti-HER2 therapy to the sequential introduction of adjuvant, neoadjuvant and post neoadjuvant approaches. This review describes key studies of systemic therapy for HER2-positive breast cancer stage I–III, which made it possible to establish clear priorities in the sequence of surgical and systemic steps, identify high risk groups which need of escalation of treatment, and determine the optimal anti-HER2 therapy for each steps, as well as de-escalation of stage I treatment without losing its effectiveness. The news from the latest cancer conferences (SABCS, ESMO, ASCO) on the impact of various biological markers on the effectiveness of anti-HER2 agents is presented. A clear concept of modern treatment of early HER2-positive breast cancer has been formed, allowing individualized approaches, and achieving better results of the therapy this aggressive biological subtype.
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Lv, Huimin, Min Yan, and Zefei Jiang. "Recent advances in the treatment of hormone receptor-positive/human epidermal growth factor 2-positive advanced breast cancer." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110133. http://dx.doi.org/10.1177/17588359211013326.
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Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive (HR+/HER2+) advanced breast cancer is a special subtype of cancer with unique features. Major guidelines recommend that combination therapy containing anti-HER2 therapy (e.g., trastuzumab and pertuzumab) should be applied as the first-line treatment for HER2+ advanced breast cancer, regardless of HR status. Endocrine therapy could be relegated to patients who cannot tolerate chemotherapy or as a post-chemotherapy empirical maintenance strategy. Previous studies have shown that the HR pathway interacts with the HER2 pathway, and the HR and HER2 pathways of endocrine therapy combined with targeted therapy can effectively avoid tumor resistance. Therefore, the combination of endocrine and targeted therapies is the preferred treatment plan for HR+/HER2+ patients to replace chemotherapy. In this review, we will discuss research progress regarding endocrine therapy combined with anti-HER2 therapy in patients with advanced breast cancer, to provide more evidence for clinical practice and broader perspectives for related research. In the future, we hope there will be more studies on HR+/HER2+ advanced breast cancer to elucidate the optimal and appropriate treatment for these patients.
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Sawaki, Masataka. "Anti-HER2 Therapy in Elderly Breast Cancer Patients." Reviews on Recent Clinical Trials 9, no. 4 (March 6, 2015): 263–66. http://dx.doi.org/10.2174/1574887109666141127102035.
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Refae, Sadal, Barbara Pistilli, and Suzette Delaloge. "Extended anti-HER2 therapy in early breast cancer." Current Opinion in Oncology 28, no. 6 (November 2016): 469–75. http://dx.doi.org/10.1097/cco.0000000000000325.
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Pondé, Noam F., Matteo Lambertini, and Evandro de Azambuja. "Twenty years of anti-HER2 therapy-associated cardiotoxicity." ESMO Open 1, no. 4 (July 2016): e000073. http://dx.doi.org/10.1136/esmoopen-2016-000073.
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Xiao, Xian, and Yingjie Jia. "Progress in anti-HER2 targeted therapy of metastatic lung cancer." E3S Web of Conferences 271 (2021): 03074. http://dx.doi.org/10.1051/e3sconf/202127103074.
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Lung cancer is one of the most common malignant tumors in the world and one of the main causes of cancer death. In lung cancer, metastatic stage accounted for a large percentage. It is a global disease affecting human health, with high incidence rate, low malignant degree and other characteristics. After decades of exploration, anti-HER2 targeted therapy in breast has made breakthrough progress, obtained encouraging clinical efficacy, and fully improved the quality of the life of patients. Because of this, more and more researchers are focusing on anti-HER2 in metastatic lung cancer targeting research. For the past few years, new targeted drugs have been constantly developed for anti-HER2 in metastatic lung cancer, and promising data results have been obtained in clinical trials and cohort study. This article provides a review of the clinical research progress of anti-HER2 targeted therapy in metastatic lung cancer in recent years, with a view to further guiding clinical treatment and providing more treatment options for patients.
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Bilani, Nadeem, Marita Yaghi, Diana Saravia, Iktej Jabbal, Maroun Bou Zerdan, Leah Elson, Hong Liang, and Zeina Nahleh. "Abstract P2-07-07: Does OncotypeDX have predictive value in HER2+ breast cancer?" Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–07–07—P2–07–07. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-07-07.
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Abstract Background: The 21-gene OncotypeDX (ODX) assay has been validated as a predictive biomarker in early-stage hormone receptor positive (HR+) and HER2- breast cancer. This multigene panel identifies patients with a high risk of recurrence who would benefit systemic treatment involving both chemotherapy and endocrine therapy, versus endocrine therapy alone. ODX is not indicated in HER2 + breast cancer. Not all patients with HER2+ breast cancer are candidates for anti-HER2 treatments due to the potential for cardiotoxicity. We were interested to assess the value of ODX in predicting benefit of anti-HER2 treatment in HR+ and HER2+ breast cancer. Methods: We used the National Cancer Database to identify patients with early-stage (AJCC clinical staging I-II), HR+/HER2+ breast cancer who happen to have received multigene testing with ODX. We described this cohort using univariate descriptive statistics. We then explored the predictive value of this biomarker by constructing two Kaplan-Meier models for overall survival (OS) with log-rank testing. The first model generates OS curves associated with different approaches to systemic treatment (a. endocrine therapy alone, versus b. endocrine therapy + anti-HER2 targeted treatment, versus c. endocrine therapy + chemotherapy, versus d. endocrine therapy + anti-HER2 targeted treatment + chemotherapy) in patients with a recurrence score (RS) < 26. The second model explores for differences in these systemic therapy approaches for those with a RS ≥ 26. Results: N=107,132 patients with early-stage, HR+/HER2+ breast cancer were included in this analysis. ODX testing was performed in n=5,280 (4.93%). The age distribution of this cohort was as follows: n=1,120 (21.2%) < 50 years, n=3,195 (60.5%) between 50-70 years, and n=965 (18.3%) were >70 years. The majority were White (84.9%), 9.6% were Black, and 3.3% were Asian. N=701 patients (13.3%) had a RS < 26, while n=4,353 (82.4%) had a RS >=26. The first Kaplan-Meier survival model indicated no significant difference in OS (p=0.445) between patients receiving different systemic treatment regimens when patients had a low risk of recurrence. However, the second Kaplan-Meier model indicates that when the ODX RS was ≥ 26, there was a statistically-significant difference in OS between systemic treatment regimens (p<0.001). 5-year OS was highest (97.4%) for patients receiving triple therapy (anti-HER2 + chemotherapy + endocrine therapy), followed by those receiving dual therapy with endocrine + anti-HER2 (96.7%), and endocrine + chemotherapy (94.9%). Patients receiving endocrine therapy alone exhibited the lowest 5-year OS (88.5%). Conclusion: Results from this large national cancer registry suggest that multi-gene testing with ODX may have predictive value in treatment selection of patients with early-stage, HR+/HER2+ breast cancer. Prospective trials are warranted to identify subgroups of patients with HR+/HER2+ breast cancer who can be spared anti-HER2 treatments and cytotoxic chemotherapy. Citation Format: Nadeem Bilani, Marita Yaghi, Diana Saravia, Iktej Jabbal, Maroun Bou Zerdan, Leah Elson, Hong Liang, Zeina Nahleh. Does OncotypeDX have predictive value in HER2+ breast cancer? [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 P2-07-07.
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Nahleh, Zeina A., Brian Hobbs, Elizabeth Elimimian, Wei (Auston) Wei, Annie Gupta, and Cassann N. Blake. "Patterns of systemic treatment utilization in ER+/PgR+/HER2+, early-stage breast cancer (BC): An analysis of the National Cancer Database." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 547. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.547.
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547 Background: The preferences and trends of treatment utilization of adjuvant endocrine therapy (ET) versus chemotherapy (CH) for small node-negative triple positive (TP) BC are unclear. We sought to determine these preferences and assess the impact on outcome. Methods: This is a retrospective study from the National Cancer Database including patients with TP stage I BC, 2004-2015. Treatment selection was evaluated for association with patient clinical and demographic characteristics using logistic regression. Overall survival (OS) was estimated using the Kaplan-Meier method and compared among patient and treatment cohorts by log-rank test and Cox regression. Results: Of 37,777 patients analyzed, 79% were White (Non-Hispanics), 10% African Americans, and 5% Hispanic/Latinos. 57% were 50-70 years old. 86% received adjuvant endocrine therapy versus 14% CH first. Around 40 % of all patients received anti-Her2 therapy. Patients younger than 70 years, with male BC, diagnosed with poorly differentiated BC, African Americans and Hispanics were more likely to be treated with chemotherapy. OS rate at 5-year was 92.3% (95% CI: 0.918-0.928). In multivariate analysis for patients with survival data, an increased rate of death was associated with: treatment in community versus academic/research centers, CH first versus ET, no treatment with anti-Her2 therapy, government versus private /no insurance, Native American ethnicity. A slight but statistically significant reduction in the in the risk of death at 5 years was evident for patients receiving anti-Her2 therapy plus ET therapy, 5-year OS 93.5% (CI: 89.2-98%), when compared to patients receiving anti-Her2 therapy plus CH 92.7 % (CI: 89.4-96). Conclusions: This study provides real world data of common practices in the US . The majority of patients with node negative Stage I, ER+/PR+/Her2+ BC received adjuvant ET and anti-Her2 therapy, not chemotherapy. These patients had a similar to slightly improved 5 year- survival when compared to anti-Her2 therapy plus CH, supporting the use ET plus anti-Her2 therapy in this setting. Future studies should focus on better selecting patients with hormone receptor positive and Her 2 + early stage BC who would benefit from adjuvant CH. Disparity in outcome also warrants further evaluation. [Table: see text]
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Shen, Xia-Bo, Jia-Yi Wu, Ke-Yu Chen, Zi-Ru Fang, Guang-Liang Li, Wei-Bin Zou, Xiaojia Wang, and Xi-Ying Shao. "Maintenance endocrine therapy prolonged progression-free survival of first-line chemotherapy with trastuzumab in advanced HR-positive, HER2-positive breast cancer patients." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e13023-e13023. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e13023.
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e13023 Background: Human epidermal growth factor receptor-2 (HER2) positive breast cancer is a growing concern due to the boom in anti-HER2 therapy. Trastuzumab as the most classic anti-HER2 therapy drug, combined with chemotherapy has become the standard first-line treatment for advanced HER2-positive (HER2+) patients. Although some real-world studies of trastuzumab have been reported, less is known about the role of hormone receptors (HR) in first-line combined therapy. For maintenance therapy after chemotherapy combined with anti-HER2 therapy, the guidance given by clinical trials is the maintenance of targeted therapy. However, for those with HER2+/HR-positive (HR+) breast cancer, whether adding endocrine maintenance therapy can benefit progression-free survival (PFS) in addition to anti-HER2 therapy still needs more research. Thus, the purpose of this study was to retrospectively analyze real-world data, determine the factors that influence the trastuzumab-based therapy in advanced HER2-positive breast cancer patients. Methods: We retrospectively collected the treatment information of advanced breast cancer patients underwent first-line chemotherapy with trastuzumab from 2012 to 2021 in Zhejiang Cancer Hospital. Kaplan–Meier analysis and Cox regression methods were used to calculate and compare the PFS. Results: The study finally enrolled 285 patients meeting the requirement, including 150 HER2+/HR-negative (HR-) and 135 HER2+/HR+ (triple-positive) patients. The median chemotherapy treatment cycles and trastuzumab cycles were 7 (6-8) and 12 (7-17) cycles, respectively. For triple-positive breast cancer, maintenance endocrine therapy was aslo given concurrently with trastusumab in 75 patients after chemotherapy and trastusumab. Overally, the median PFS of first-line treatment was 11.73 (10.16-13.30) months, which was consistent with literature reports. Multivariate analysis revealed that HR positive [hazard ratio, 0.69; 95% confidence interval (CI), 0.52–0.92; P= 0.010], and non-brain metastasis (hazard ratio, 0.54; 95% CI, 0.29–0.99; P= 0.048) were independent prognostic factors. Further Kaplan–Meier analysis demonstrated triple-positive patients with maintenance endocrine therapy significantly had longer PFS than triple-positive patients without maintenance endocrine therapy and HER2+/HR- patients (21.33m vs. 10.13m vs. 9.53m, respectively, P < 0.001). Conclusions: HR-positive was an independent prognostic factor for HER2-positive advanced breast cancer patients receiving first-line chemotherapy with trastuzumab. And endocrine therapy combined trastuzumab as Maintenance after chemotherapy prolonged PFS in HR-positive subgroup patients.
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Moyer, Cassandra L., Abhijit Mazumdar, Jamal Hill, Martin E. Sanders, and Powel Brown. "Abstract P4-01-14: The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–01–14—P4–01–14. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-01-14.
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Abstract Background: HER2 targeted monoclonal antibodies and tyrosine kinase inhibitors (TKI) are effective treatments for HER2-amplified primary tumors. However, the challenge persists that primary and acquired resistance to anti-HER2 therapy is common, and that anti-HER2 targeted therapies fail to achieve a cure in the metastatic setting. There is a critical need for safe and effective therapies that can overcome anti-HER2 drug resistance and eliminate breast cancer metastases. Here, we present data demonstrating the activity of IRX4204, a highly specific agonist of the nuclear retinoid X receptor (RXR), to inhibit the growth of HER2-amplified breast cancer cell lines alone and in combination with current anti-HER2 therapies. Methods: In vitro cell growth assays were conducted to evaluate the efficacy of IRX4204 alone and in combination with trastuzumab, tucatinib, neratinib or T-DM1, using a panel of breast cancer cell lines expressing various levels of HER2. A calculated coefficient of drug interaction (CDI) and isobologram analysis was used to assess the additive, synergistic or antagonistic effects of IRX4204 with each anti-HER2 targeted therapy. Results: IRX4204 treatment alone inhibited the growth of HER2-overexpressing cell lines, SkBr3, AU565, HCC1419 and ZR75-1 in vitro, but not the growth of HER2-normal cell lines MCF7, MDA-MB-231, or HCC1143. When combined with trastuzumab, tucatinib, neratinib or T-DM1, additive or synergistic effects were observed in all of the drug-sensitive cell lines. Moreover, IRX4204 in combination with neratinib or tucatinib inhibited the growth of a TKI-resistant breast cancer cell line (HCC1954). Conclusion: These data demonstrate a novel use of an RXR agonist, IRX4204, to inhibit the growth of HER2-amplified breast cancer cell lines and to enhance the activity of anti-HER2 therapy in vitro. These results also demonstrate that IRX4204 can overcome anti-HER2 resistance to inhibit the growth of HER2-positive cells. These data demonstrate that IRX4204 can enhance the anti-cancer activity of anti-HER2 therapies even in TKI-resistant cells. In vivo experiments and mechanistic studies are ongoing. Citation Format: Cassandra L Moyer, Abhijit Mazumdar, Jamal Hill, Martin E Sanders, Powel Brown. The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer [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 P4-01-14.
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Espinosa Fernandez, Jose Rodrigo, Teruo Yamauchi, Chiyo K. Imamura, Hideko Yamauchi, Hiromitsu Jinno, Maiko Takahashi, Yuko Kitagawa, et al. "Comprehensive assessment of cancer stem cell like cells in prediction of pathologic complete response to preoperative dual anti–HER2 therapy for HER2–positive primary breast cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e12123-e12123. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12123.
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e12123 Background: Chemotherapy for breast cancer destroys non–stem cells while sparing cancer stem cells (CSCs). In contrast, anti–HER2 therapy may eliminate resistant cells because HER2 may be a key driver of CSCs. CSC biomarkers have been found to be prognostic of poor outcome and predictive of resistance to therapy. However, there are no comprehensive studies of the impact of anti-HER2 therapies on CSC–related biomarkers. We conducted a prospective biomarker determination study of breast CSCs characterized by CD44v expression and increased aldehyde dehydrogenase 1 (ALDH1) enzymatic activity or expression. Methods: In a prospective trial (ClinicalTrials.gov: NCT01688609), 18 patients with operable primary HER2+ breast cancer (≥T2 excluding inflammatory, any N; median age of 54 yrs) were treated with preoperative anti–HER2 therapy following the NeoALTTO trial dual therapy arm regimen, with a goal of identifying novel predictive biomarkers for pCR. Proportions of tumor cells with CSC characteristics, defined as CD44v+ and ALDH1+, were estimated at baseline, at 6 weeks (after therapy with lapatinib/trastuzumab) and at 18 weeks (after therapy with lapatinib/trastuzumab and paclitaxel) to assess adaptive response. We determined changes in the quantity and characteristics of CSC–related biomarkers during preoperative therapy and correlated them to tumor response. Results: Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v staining on tumor cells at baseline and none were positive on the 6–week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p = 0.0128). ALDH1 expression and other biomarkers were not statistically significant predictors of pCR. Conclusions: Enrichment of CD44v+ tumor cells after double anti–HER2 therapy may predict poor response to dual anti–HER2 therapy with cytotoxic chemotherapy. A second biopsy after the start of preoperative therapy may reflect biological changes useful for the guidance and application of therapeutic strategies for patients with HER2+ breast cancer. Clinical trial information: NCT01688609.
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Meisel, Jane Lowe, Vyshak Alva Venur, Michael Gnant, and Lisa Carey. "Evolution of Targeted Therapy in Breast Cancer: Where Precision Medicine Began." American Society of Clinical Oncology Educational Book, no. 38 (May 2018): 78–86. http://dx.doi.org/10.1200/edbk_201037.
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As we consider best practices and approaches to targeted therapy in the clinic and in terms of trial design, breast cancer can serve as a useful model for other disease types, because estrogen receptor–positive and HER2-positive breast cancer have been known entities for several decades. In this review, we provide a history of the development of anti-estrogen therapy and anti-HER2–directed therapy and we discuss our growing understanding of resistance to targeted therapy as seen through this lens. We highlight some of the recent breakthroughs that have enhanced our understanding of resistance to endocrine and anti-HER2 therapy, and we discuss some of the ongoing research in the field.
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Zhu, X., and S. Verma. "Targeted therapy in her2-positive metastatic breast cancer: a review of the literature." Current Oncology 22 (January 15, 2015): 19. http://dx.doi.org/10.3747/co.22.2363.
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Breast tumours positive for her2 (human epidermal growth factor receptor 2) represent approximately 20% of all breast cancer cases and are associated with an aggressive natural history. The advent of targeted anti-her2 therapies has dramatically improved disease control and survival in patients with metastatic her2-positive breast cancer. Targeted agents are now considered the standard of care in the first-line setting and beyond.The present review summarizes the currently available data on targeted anti-her2 therapies from completed randomized phase iii clinical trials andbriefly discusses emerging advances that will address unmet needs in metastatic her2-positive breast cancer.
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Yang, Jixin, Yuqing Yang, Xinxin Wen, Jiang Wu, Jing Yu, Lei Wang, Meiling Huang, Wenyu Hu, Wen Ma, and Nanlin Li. "Neoadjuvant pegylated liposomal doxorubicin (PLD) plus cyclophosphamide followed by nab-paclitaxel (Nab-P) as primary chemotherapy continuously combined with dual HER2 blockage for HER2-positive breast cancer: A single-arm phase 2 trial (Brecan Trial)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e12622-e12622. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e12622.
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e12622 Background: Despite that AC-THP regimen is one of the commonly used regimens for neoadjuvant treatment of HER2-positive breast cancer, previous studies showed that pCR rate rarely exceeds 70%. We hypothesized that prolonged dual anti-HER2 therapy can increase pCR rate in neoadjuvant therapy. In this study, we designed a single-arm trial of ACHP-THP regimen (continuous dual anti-HER2 therapy of trastuzumab and pertuzumab) in neoadjuvant therapy of HER2 positive breast cancer. To minimize adverse cardiovascular events, we used pegylated liposomal doxorubicin (PLD) and Nab-Paclitaxel (Nab-P) instead of doxorubicin and paclitaxel. We aimed to examine whether continuous dual anti-HER2 therapy can boost pCR rate in the neoadjuvant therapy. The cardiotoxicity was closely monitored when the anti-HER2 therapy was combined with PLD and Nab-P respectively. Methods: Upon approval by the Medical Ethics Committee of Xijing Hospital, patients with HER2-positive breast cancer (cT2-3/N0-1/M0) receiving neoadjuvant therapy, were enrolled. The patients were treated with PldCHP (pegylated liposomal doxorubicin 35mg/m2, cyclophosphamide 600mg/m2, trastuzumab 8 mg/kg loading, then 6 mg/kg, pertuzumab 840 mg loading, then 420 mg, iv, q3w) for 4 cycles followed by Nab-PHP (Nab-Paclitaxel 260mg/m2, trastuzumab 6 mg/kg, pertuzumab 420 mg, iv, q3w) for 4 cycles, with strict monitoring of cardiotoxicity. The primary endpoint was pCR rate, and secondary endpoint was cardiotoxicity during neoadjuvant therapy. Results: From January 2020 to October 2021, a total of 96 patients were recruited. Among the 96 patients with a median age of 49 (21-71), 58 patients were HR positive and 42 patients had positive lymph node status. Overall, the pCR rate was 80.2% (77/96). The ER-positive tumor achieved a higher pCR rate than ER-negative tumor (82.8% vs 76.3%, p=0.439), but the difference was statistically insignificant. Multivariate regression analysis showed that for participants older than 30, HER2 3+ (IHC) showed a statistically significant positive influence on pCR rate. The common adverse reactions of grade ≥3 were neutropenia (30.2%), asthenia (8.3%), and peripheral sensory neuropathy (7.3%). Left ventricular insufficiency was detected in 4 patients, and no cardiotoxic events higher than grade 2 occurred during the neoadjuvant therapy. There was no treatment-related death. Conclusions: The PldCHP---Nab-PHP regimen is a feasible and effective neoadjuvant therapy for early stage HER2-positive breast cancer, showing high pCR rate and acceptable cardiotoxicity. These results support a further random controlled trial testing for continuous dual anti-HER2 therapy combined with PLD in neoadjuvant or adjuvant therapy of HER2 positive breast cancer.
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Sarode, Venetia, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, and Barbara Haley. "Abstract P1-02-14: A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–02–14—P1–02–14. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-02-14.
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Abstract A comparative analysis of clinical and pathologic characteristics of HER2 positive breast cancer patients treated with adjuvant versus neoadjuvant antiHer2 therapy: an analysis of 397 cases. Introduction: Currently there are several anti-HER2 therapy options for patients with HER2 positive breast cancer. Surgery as an initial treatment is usually performed in patients with smaller, node negative tumors. Neoadjuvant therapy (NAT) is the treatment of choice for patients with higher stage disease. Detailed analysis of clinical and pathologic characteristics of patients who received adjuvant versus NAT anti-HER2 therapy has not been well elucidated. Objectives: A comparative analysis of clinical and pathologic findings including biomarker expression (ER, PR, HER2 and Ki67) was performed to determine if there were differences in tumor characteristics and clinical outcome in the two groups.Methods:We retrospectively analyzed data on HER2+ breast cancer patients treated with adjuvant and NAT anti-HER2 therapy from 2011 to 2017. Clinical and pathologic parameters including biomarker expression prior to the start of therapy were obtained from the electronic database after IRB approval. In the adjuvant group, patients were treated with initial surgery followed by anti-HER2 therapy plus chemotherapy. In the NAT group, anti-HER2 therapy plus chemotherapy was administered prior to definitive surgery. Types of anti-HER2 therapies and follow-up information were obtained from the electronic medical record. Results:We identified 258 (64.9%) patients who received NAT and 139 (35.0%) received adjuvant anti-HER2 therapy. Table 1.VariablesNeoadjuvant groupAdjuvant groupp-valueAgeBelow 40 years42 (16.2%)11(7.9%)0.02940 years and above Total216 (83.7%) 258128 (92.0%) 139Menopausal statusPremenopausalPostmenopausal Total113 (45.3%)136 (54.6%) 24935 (25.1%)104 (74.8%) 139<0.001Nodal status on biopsyNegativePositive Total31 (18.1%)140 (81.8%) 17117 (53.1%)15 (46.8%) 32<0.001Tumor size by imaging (cm)Mean + SD3.87+2.832.24+1.76<0.001Tumor grade123 Total5 (2%)78 (31.3%167 (66.8%) 2507 (5.3%)49 (37.6%)74 (56.9%) 1300.068HER2 by IHC0 and 1+ (FISH +)2+ (FISH+)3+ Total11 (4.2%)61 (23.8%)184 (71.8%) 2564 (3.5%)41 (36.6%)67 (59.8%) 1120.042HER2 FISH copy no.Mean +SD15.44 ± 8.2512.64 ± 6.470.007HER2 ratioMean SD6.35 ± 3.445.57 ± 3.560.046ER statusNegativePositive Total113 (43.9%)144 (56.0%) 25745 (35.1%)83 (64.8%) 1280.122Percent positive71.38 ± 33.3778.74 ± 29.040.042ER intensity1+2+3+ Total24 (16.9%)38 (26.7%)80 (56.3%) 1422 (2.6%)26 (34.2%)48 (63.1%) 760.001PR statusNegative Positive Total147 (57.1%)110 (42.8%) 25766 (51.9%)61 (48.0%) 1270.389Percent positive42.33 ± 34.5444.72 ± 32.890.645PR intensity1+2+3+ Total20 (18.5%)41 (37.9%)47 (43.5%) 10810 (17.5%)30 (52.6%)17 (29.8%) 570.012KI67 indexPercent positive49.44 ± 22.6638.56 ± 22.36<0.001Anti-HER2 therapyHerceptinHerceptin+ Perjeta Total72 (31.0)160 (68.9%) 23291 (89.2%)11 (10.7%) 102<0.001SurgeryTotal Partial BilateralModified radicalOther Total SurvivalAlive. Dead116 (44.95)75 (29.0%)25 (9.6%)38 (14.7%)04 (1.5%) 258 239 (92.6%) 19 (7.3%)55 (40.4%)56 (41.1%)18 (13.2%)5 (3.6%)02 (1.4%) 136 125 (89.9%) 14 (10.0%)0.002 0.458Conclusions:Patients who received NAT were significantly younger, premenopausal with more aggressive tumor biology (higher Ki67, HER2 expression). Recent advances in anti-HER2 therapy has improved the outcome of these patients despite having higher stage disease. Breast conserving surgery was higher in the adjuvant group since the tumors were smaller in size. There was no significant difference in overall survival when compared to the adjuvant group (p=0.458) Citation Format: Venetia Sarode, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, Barbara Haley. A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases [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 P1-02-14.
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Goldner, Marcelle, Maria A. Franzoi, Lissandra D. Lago, and Noam Pondé. "Anti-HER2 therapy for breast cancer in older patients." Future Oncology 16, no. 19 (July 2020): 1393–407. http://dx.doi.org/10.2217/fon-2020-0036.
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Older patients now form between 30 and 40% of breast cancer (BC) patients. Managing older patients with BC is particularly challenging due to the limited availability of high-quality evidence. In this review we discuss the available evidence on the efficacy and safety of anti-HER2 agents in older patients with HER2-positive BC is presented, with a particular look at the latest results of promising new agents such trastuzumab-deruxtecan. The data suggest that older patients can expect similar efficacy when using standard regimens, with higher toxicity, particular cardiac toxicity and diarrhea. Anti-HER2 agents should thus be used in most older patients most as per standard of care as long as adequate follow-up is available to manage toxicities.
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Johnson, Kai Conrad Cecil, Ai Ni, Michael Grimm, Sagar D. Sardesai, Daniel G. Stover, Mathew Amprayil Cherian, Margaret Elena Gatti-Mays, et al. "The survival benefit of anti-HER2 treatment in the management of small (T1mic, T1a, T1b, T1c), node-negative HER2+ breast cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 532. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.532.
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532 Background: Limited compelling prospective and retrospective data regarding the added benefit of anti-HER2 therapy in the management of small, node-negative HER2-positive breast cancer (HER2+BC) exists, in part due to differences in outcome reporting, unmatched analyses, and a lack of head-to-head comparisons. As a result, national guideline committees find themselves unable to confidently recommend anti-HER2 therapy and clinicians are left to exercise clinical judgement on whether the use of anti-HER2 therapy should be considered for such patients. Methods: Our team performed a multi-institutional retrospective analysis using the ASCO CancerLinQ database, with a focus on clinical data from small, node-negative HER2+BC patients diagnosed between 2010 to 2021. We compared clinical outcomes between those who received adjuvant trastuzumab therapy, with or without chemotherapy, to those who did not, with our primary outcomes being invasive disease-free survival (iDFS) and overall survival (OS). We performed both a univariate and multivariate analysis, using a Cox proportional hazard model to control for factors including age, ethnicity, body mass index, hormone status, tumor grade, histology type, BRCA status, region, and smoking history. Additionally, a three-arm univariate analysis was performed comparing untreated patients to trastuzumab alone versus combination therapy. Results: In total, 1206 patients met inclusion criteria, including 779 patients who received trastuzumab with or without chemotherapy. We found a statistically significant improvement in both iDFS (HR 0.73, p = 0.01) and OS (HR 0.63, p = 0.027) on univariate analysis for those receiving anti-HER2 therapy. Similarly on multivariate analysis, iDFS (HR 0.75, p = 0.030) and OS (HR 0.61, p = 0.029) were improved in those who received therapy, regardless of tumor size. Our three-arm univariate analysis involving no treatment (n = 427), trastuzumab monotherapy (n = 169), and combination therapy (n = 578) found that iDFS was significantly improved for both treatment arms compared to observation alone (p = 0.006), whereas OS trended towards significance in the treatment arms but did not reach this target (p = 0.061). No significant difference was noted between treatment arms. Conclusions: Our analysis found a statistically significant improvement in iDFS and OS when patients with small, node negative, HER2+BC received adjuvant anti-HER2 therapy with or without chemotherapy as compared to observation. From our univariate three-arm comparison, it appears that trastuzumab provides the majority of benefit to patients in terms of DFS, but this result is exploratory. Further investigation is warranted, including meta-analyses to better characterize the degree of benefit seen with anti-HER2 treatment. For now, this data adds to evidence suggesting added benefit with therapy over observation.
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Jeong, Hwa Yeon, Hyeri Kim, Myunghwa Lee, Jinju Hong, Joo Han Lee, Jeonghyeon Kim, Moon Jung Choi, Yong Serk Park, and Sung-Chun Kim. "Development of HER2-Specific Aptamer-Drug Conjugate for Breast Cancer Therapy." International Journal of Molecular Sciences 21, no. 24 (December 21, 2020): 9764. http://dx.doi.org/10.3390/ijms21249764.
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In this study, HER2 RNA aptamers were conjugated to mertansine (DM1) and the anti-cancer effectiveness of the conjugate was evaluated in HER2-overexpressing breast cancer models. The conjugate of HER2 aptamer and anticancer drug DM1 (aptamer-drug conjugate, ApDC) was prepared and analyzed using HPLC and mass spectrometry. The cell-binding affinity and cytotoxicity of the conjugate were determined using confocal microscopy and WST-1 assay. The in vivo anti-tumoral efficacy of ApDC was also evaluated in mice carrying BT-474 breast tumors overexpressing HER2. The synthesized HER2-specific RNA aptamers were able to specifically and efficiently bind to HER-positive BT-474 breast cancer cells, but not to HER2-negative MDA-MB-231 breast cancer cells. Also, the HER2-specific ApDC showed strong toxicity to the target cells, BT-474, but not to MDA-MB-231 cells. According to the in vivo analyses drawn from the mouse xenografts of BT-747 tumor, the ApDC was able to more effectively inhibit the tumor growth. Compared to the control group, the mice treated with the ApDC showed a significant reduction of tumor growth. Besides, any significant body weight losses or hepatic toxicities were monitored in the ApDC-treated mice. This research suggests the HER2 aptamer-DM1 conjugate as a target-specific anti-cancer modality and provides experimental evidence supporting its enhanced effectiveness for HER2-overexpressing target tumors. This type of aptamer-conjugated anticancer drug would be utilized as a platform structure for the development of versatile targeted high-performance anticancer drugs by adopting the easy deformability and high affinity of aptamers.
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Watanabe, Kenichi, Kanako Hagio, Motoi Baba, Mayuko Ikarashi, Masako Sato, Nobumoto Tomioka, and Masato Takahashi. "Anti-HER2 therapy for HER2-positive metastatic breast cancer: regimens and treatment outcomes." Annals of Oncology 26 (November 2015): vii143. http://dx.doi.org/10.1093/annonc/mdv472.166.
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Ross, J. S. "Breast cancer biomarkers and HER2 testing after 10 years of anti-HER2 therapy." Drug News & Perspectives 22, no. 2 (2009): 93. http://dx.doi.org/10.1358/dnp.2009.22.2.1334452.
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Masuda, Takahito, Hiroshi Fujimoto, Ryotaro Teranaka, Masayuki Kuroda, Yasuyuki Aoyagi, Takeshi Nagashima, Takafumi Sangai, et al. "Anti-HER2 antibody therapy using gene-transduced adipocytes for HER2-positive breast cancer." Breast Cancer Research and Treatment 180, no. 3 (March 2, 2020): 625–34. http://dx.doi.org/10.1007/s10549-020-05581-x.
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Zhang, Jingwei, Adam J. Pearson, Nitin Sabherwal, Brian A. Telfer, Nisha Ali, Karmern Kan, Qiuping Xu, et al. "Inhibiting ERK5 Overcomes Breast Cancer Resistance to Anti-HER2 Therapy By Targeting the G1–S Cell-Cycle Transition." Cancer Research Communications 2, no. 3 (March 2022): 131–45. http://dx.doi.org/10.1158/2767-9764.crc-21-0089.
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Targeting HER2 has become a landmark in the treatment of HER2-driven breast cancer. Nonetheless, the clinical efficacy of anti-HER2 therapies can be short-lived and a significant proportion of patients ultimately develop metastatic disease and die. One striking consequence of oncogenic activation of HER2 in breast cancer cells is the constitutive activation of the extracellular-regulated protein kinase 5 (ERK5) through its hyperphosphorylation. In this study, we sought to decipher the significance of this unique molecular signature in promoting therapeutic resistance to anti-HER2 agents. We found that a small-molecule inhibitor of ERK5 suppressed the phosphorylation of the retinoblastoma protein (RB) in HER2-positive breast cancer cells. As a result, ERK5 inhibition enhanced the antiproliferative activity of single-agent anti-HER2 therapy in resistant breast cancer cell lines by causing a G1 cell-cycle arrest. Moreover, ERK5 knockdown restored the antitumor activity of the anti-HER2 agent lapatinib in human breast cancer xenografts. Taken together, these findings support the therapeutic potential of ERK5 inhibitors to improve the clinical benefit that patients receive from targeted HER2 therapies. Significance: Here we demonstrate that targeting ERK5 in HER2-positive breast cancer cells reduces the level of phosphorylation of RB, an important mediator of the G1–S transition. This effect is associated with increased antitumor activity of lapatinib in combination therapy with ERK5 silencing. Collectively, these findings reveal that ERK5 constitutes a relevant therapeutic target for the many patients with resistant HER2-positive breast cancer.
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Choi, Jae Hyeog, Ki Hyang Kim, Kug Hwan Roh, Hana Jung, Su Kil Seo, Il Whan Choi, Sung Su Yea, and SaeGwang Park. "Combination therapy of a PI3K p110α-isoform-selective inhibitor and anti-HER2/neu antibody enhances the anti-tumor immunity in breast cancer mouse model." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 204.9. http://dx.doi.org/10.4049/jimmunol.198.supp.204.9.
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Abstract Trastuzumab (Herceptin) is a humanized recombinant monoclonal antibody against HER2 that has shown the clinical benefit in HER2+ breast cancer patients. Because non-responders to trastuzumab have been observed, one strategy to overcome the resistance is combination therapy. Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-HER2/neu antibody) are effective against HER2+ breast cancer mouse model. The therapeutic effect and anti-tumor immunity of combination therapy with an anti-HER2/neu antibody and a pan-PI3K inhibitor (GDC-0941) or a p110a isoform-selective inhibitor (A66) was evaluated in vivo breast cancer models. Combined the anti-neu and PI3Ki treatment synergistically occurred in anti-tumor immunity and HER2/neu-mediated memory T cell responses. In the presence of the anti-neu antibody, A66 was more effective in increasing the T cells and IFN-γ+ CD8+ T cells in TILs. IFN-γ ELISPOT data showed that tumor-specific T cells against neu and non-neu tumor antigens increased synergistically after combination PI3Ki and anti-neu treatment, and A66 was more potent. In a TUBO (neu+) and TUBO-P2J (neu-) mixed model representing IHC2+ tumors, A66 showed greater tumor mass control and survival prolongation than GDC-0941, when combined with the anti-neu antibody. Combined with the anti-neu antibody, A66 was more effective than GDC-0941, and A66 synergized with the anti-neu antibody in terms of anti-tumor immunity. We propose A66 plus anti-HER2/neu antibody as an effective strategy in trastuzumab-resistant breast cancers.
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Gámez-Chiachio, Manuel, Carmen Ramos-Nebot, Ángela Molina-Crespo, Pérez-Torres Bárbara, Lidia Martínez, David Sarrió, and Gema Moreno- Bueno. "Gasdermin B over-expression modulates HER2-targeted therapy resistance through LC3B/Rab7 interaction." IBJ Plus 1, s5 (June 3, 2022): 23. http://dx.doi.org/10.24217/2531-0151.22v1s5.00023.
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Tumor resistance to therapy is one of the most important challenges in current oncology. A clear example of this major issue is the HER2-positive tumors characterized by ERBB2 (HER2/neu) overexpression. HER2+ overexpression/ amplification occurs in several tumors, especially in breast and gastric carcinomas that show an aggressive phenotype traditionally associated to poor prognosis. In fact, despite the clinical outcome of these tumors has gradually improved, due to the development of different antiHER2 therapies, many patients will not respond to these treatments or develop acquired resistance. Several potential resistance mechanisms to these targeted therapies have been described. Among them, our laboratory established, for the first time, that the amplification/overexpression of Gasdermin B (GSDMB), which occurs in more than 60% HER2+ breast cancer patients, is a marker of poor prognosis. Moreover, our data in HER2+ tumors revealed that GSDMB overexpression correlated to distant metastasis, poor clinical outcome, and reduced response to anti-HER2 therapies. In this context, we have attempted to elucidate the molecular mechanism whereby GSDMB collaborates in the resistance to anti-HER2 therapies. To decipher the functional relevance of GSDMB in promoting resistance to HER2-targeted therapies we performed several molecular approaches (immunoblot, flow cytometry, immunoprecipitation, etc.) in different breast and gastric carcinoma cell models. Finally, we validated the efficacy of the identified targeted treatment using two complementary in vivo preclinical models (mice and zebrafish). Our results confirmed that similarly to HER2 breast tumors, GSDMB is also over-expressing in more than 50% in HER2 gastric tumors. Furthermore, this over-expression renders HER2 breast and gastric cancer cells more resistant to anti- HER2 agents by promoting protective autophagy. Consistent with this, we proved that the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response specifically in GSDMB-positive tumors in vitro and in vivo. Mechanistically, we also confirmed that GSDMB forms a complex with LC3B and Rab7. Finally, we validated these results in clinical samples of HER2 breast and gastric cancers, where GSDMB/LC3B/Rab7 co- expression associates significantly with relapse. In conclusion, our data decipher the molecular mechanism that underlies the relation between Gasdermin B and pro-survival autophagy with the final goal of finding a therapy that would be effective in overcoming resistance to anti-HER2 standard therapies in HER2/GSDMB+ tumors.
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Guiu, S., M. A. Mouret Reynier, M. Toure, and B. Coudert. "Predictive Factors of Response in HER2-Positive Breast Cancer Treated by Neoadjuvant Therapy." Journal of Oncology 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/854121.
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Since 2005, major progresses have been made in the neoadjuvant treatment of HER2-positive breast cancer. Trastuzumab introduction associated with chemotherapy has been the first major step leading to the improvement of the complete pathological response rate and, like in the adjuvant studies, better survivals. Dual HER2 blockade has been the next step and trastuzumab is associated now with other anti-HER2 therapies like lapatinib or pertuzumab, the latter being much more easy to use in combination with chemotherapy. Additional knowledge is necessary to better define within the HER2 tumor subgroup which patients could benefit more from targeted therapies. Different biomarkers have been studied to predict the response after anti-HER2 neoadjuvant therapies but until now none has been validated.