HER2-positive Early Breast Cancer Research Articles

Incidence and prognostic impact of HER2-positivity loss after dual HER2-directed neoadjuvant therapy for HER2+ breast cancer.

Loss of HER2 "positivity" can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2-positivity loss after neoadjuvant dual HER2-targeted treatment plus chemotherapy, the current standard-of-care for most early stage HER2-positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2-low category. In this retrospective study, we determine the incidence and prognostic impact of HER2-positivity loss, including the evolution to HER2-low disease, after neoadjuvant dual HER2-targeted therapy with chemotherapy. Clinicopathologic data for patients with stage I-III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2-targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated. A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2-positive and 25 (41.0%) had HER2-negative residual disease. Of the 25 patients with HER2-negative residual disease, 22 (88%) of patients were classified as HER2-low. After a median follow-up of 3.3 years, patients who retained HER2-positivity after neoadjuvant treatment had a 3-year IDFS rate of 91% (95% CI, 91%-100%), while patients who lost HER2-positivity had a 3-year IDFS rate of 82% (95% CI, 67%-100%). Almost half of patients with residual disease following neoadjuvant dual HER2-targeted therapy plus chemotherapy lost HER2-positivity. The loss of HER2-positivity may not confer negative prognostic impact, although the results were limited by short follow-up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.

Favorable Outcome and Safety of Neoadjuvant Trastuzumab Emtansine (T-DM1) in a HER2-Positive Early Breast Cancer Patient with Severe Renal Disease on Hemodialysis Ineligible for Conventional Chemotherapy: A Case Report

Breast cancer is the leading cause of cancer-related death among women worldwide. It is the most common malignancy in middle-age and elderly women already suffering from other comorbidities, such as chronic kidney disease (CKD). Being a heterogeneous disease, it has variable subtype-specific outcomes and responses towards treatment. Patients with human epidermal growth factor receptor 2 (HER2) overexpression are treated with anti-HER2-targeted drugs. With the advent of newer drugs, the usage of HER2 blockade and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer management helps to increase the probability of achieving pathological complete response. We herein present a case of a patient with breast cancer with long-standing CKD and on maintenance hemodialysis where treatment with conventional chemotherapy regimens was a concern and managed with an antibody–drug conjugate (ADC), namely T-DM1, in a neoadjuvant setting. The patient showed a favorable outcome, and the tolerance of T-DM1 in this patient was predictable. This is a first-of-its-kind case report, where T-DM1 was used in a neoadjuvant setting for a patient on simultaneous hemodialysis.

Abstract OT2-14-01: Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial

Abstract Objective: Trastuzumab-based adjuvant therapy was demonstrated to improve the prognosis of early human epidermal growth factor receptor 2 (HER-2) positive breast cancer, while about 10% of patients showed primary resistance. ExteNET study showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in women with HER2-positive breast cancer. Besides, for patients with early hormone receptor positive breast cancer within 1 year of prior trastuzumab with residual disease after neoadjuvant therapy, extended adjuvant neratinib showed prolonged overall survival, which suggested the potential benefit of extended adjuvant therapy for high-risk patients. Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting epidermal growth factor receptor, HER2, and HER4, which showed promising efficacy and manageable safety profiles in the treatment of HER-2 positive advanced breast cancer. In this study, we aimed to evaluate the efficacy and safety of extended adjuvant pyrotinib following trastuzumab-based adjuvant therapy in patients with high-risk early HER-2 positive breast cancer. Methods: In this ongoing multicenter, open-label, phase II trial at 23 centers in China, women with operable high-risk early HER-2 positive breast cancer and known hormone receptor status, who have completed trastuzumab-based adjuvant therapy within 6 months were enrolled. High-risk patients must meet one of the following criteria: N stage ≥1; T stage ≥2; did not achieve pathological complete response (pCR) after neoadjuvant therapy; had pCR after neoadjuvant therapy but with tumor size ≥ 5cm or N stage ≥2; or tumor size less than 2cm but with high Ki67, histologic grade 3 or with lymph node micrometastasis. Eligible patients were assigned to receive 6 month or 1 year of oral pyrotinib 400mg/day. The primary endpoint was the 2-year iDFS rate. Results: Between January, 2019 and February, 2022, a total of 142 eligible women were enrolled and assigned to receive pyrotinib, with a median age of 50 (range: 25-72) years old. Ninety-seven patients had a T stage ≥2. A total of 108 patients (76.1%) had node-positive disease, and 64 (45.1%) were hormone receptor positive. Twenty-five patients used neoadjuvant therapy previously, and all of them did not receive pCR (Table 1). After a median follow-up of 20 (range: 0.25-41) months, the 2-year iDFS rate was not available. Two and four patients reported invasive disease events after 6-month and 1-year of follow-up, with the 6-month and 1-year iDFS rates of 98.6% and 97.2%, respectively. The most common adverse events reported was diarrhea (78.2%), followed by fatigue (36.6%), lymphocyte count decreased (36.6%), nausea (33.1%) and hand-foot syndrome (33.1%). Forty-three patients experienced grade 3 diarrhea, and no grade 4 or higher adverse event was reported (Table 2). Adverse event leading to treatment discontinuation occurred in 12 (8.5%) patients. Conclusion: Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy was well-tolerated and showed potential efficacy in high-risk early HER-2 positive breast cancer. The follow-up is ongoing to determine the long-term benefit of extended adjuvant pyrotinib. Table 1. Baseline characteristics of patients ER: estrogen receptor; PR: progesterone receptor. Table 2. Treatment-emergent adverse event occurring in at least 10% of the patients Citation Format: Feilin Cao, Zhaosheng Ma, Guinv Hu, Xiaotao Zhu, Shuguang Li, Shuzheng Chen, Binglie Chen, Zhanwen Li, Weizhu Wu, Xiaochun Ji, Jingde Shu, Deyou Tao, Xiaoqing Hu, Min Zheng, Ouchen Wang, Qingjing Feng, Jing Hao, Xujun Li. Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-14-01.

Abstract P4-07-55: Neoadjuvant trastuzumab and pertuzumab in combination with anthracyclines in HER2-positive early breast cancer: real-world data on effect of body mass index in cardiac safety

Abstract BACKGROUND: Neoadjuvant therapy with trastuzumab and pertuzumab (HP) combined with chemotherapy (ChT) is the standard of care in ≥ cT2cN0 or N+ HER2-positive early breast cancer (EBC). Although cardiotoxicity is a known adverse effect of anti HER2-therapy and anthracyclines, recently BERENICE final analysis showed cardiac safety of HP in combination with standard or dose-dense anthracycline-based ChT. However, real-world data is lacking, specifically in patients (pts) with identified cardiovascular (cv) risk factors. Our study aimed to evaluate cardiac safety of HP and anthracyclines in HER2+ EBC and explore potential impact of body mass index (BMI). METHODS: This retrospective analysis included HER2+ EBC pts receiving neoadjuvant HP and anthracycline- and taxane- based ChT, at our institution, between 2016 and 2021. Baseline clinical, demographic, histopathological and immunohistochemical features were reported. Pts were categorized as underweight (< 18.5kg/m2), normal (≥18.5;< 25kg/m2), overweight (≥25;< 30kg/m2) and obese (≥30kg/m2), according to basal BMI WHO categories. The primary objective was to evaluate cardiac safety, assessed by incidence of left ventricular ejection fraction (LVEF) declines (≥10% from baseline and to a value < 50%) and NYHA class III/IV heart failure. Univariate and multivariate logistic regression analysis were performed using BMI as a categorical variable. Safety data were compared in subgroup analyses for underweight/normal and overweight/obese pts. Statistics were performed with IBM™ SPSS software, version 23. RESULTS: Our analysis enrolled 112 female pts, with a median age of 54 years (30-78), including 22pts (19.6%) with ≥65years and 55 (49.1%) postmenopausal women. Most pts (n=89; 79.5%) had HR-positive disease. 44pts (39.3%) had stage II and 68pts (60.7%) had stage III disease. According to BMI, pts were classified as underweight (n=3; 2.7%), normal (n=40; 35.7%), overweight (n=47; 42%) and obese (n=22; 19.6%). No association was found between BMI and tumor stage (p=0.829), grade (p=0.753) and HR status (p=0.212). Other baseline cv risk factors were identified: former/active smoker (n=34;30.4%), diabetes (n=10;8.9%), hypertension (n=30;26.8%), and dyslipidemia (n=32;28.6%). Most pts had ≥2 cv risk factors (n=66;58.9%). Two diferent regimes were used FEC100-D+HP (2016-2019, n=84) and ddAC-wkPaclitaxel+HP (2020-2021, n=28). Overall, pCR was achieved in 62 pts (55.4%). Regarding cardiac safety evaluation, 4 pts (3.6%) experienced at least one LVEF decline ≥10% from baseline and to a value < 50%, including 3 pts that were overweight/obese. Declines were reversible in all pts, with recovery by next assessment. Two pts (1.8%) experienced one NYHA class III heart failure event. Both pts were overweight/obese and had another concomitant risk factor for cardiovascular disease. Both pts discontinued treatment. No statistically significant association was found between overweight/obesity and cardiac events (OR 1.26, 95%CI 0.22-7.20; p=0.792). Median follow-up duration was 39 months. No new safety signals were identified. CONCLUSION: Cardiac safety of neoadjuvant HP in combination with anthracyclines in HER2-positive EBC in our real-world data is consistent with previous studies. Despite most cardiac events occurred in overweight/obese pts, no statistically significant effect was found. Further studies are needed to evaluate cardiotoxicity in pts with cv risk factors and evaluate impact of therapeutic interventions. Citation Format: Diana Simão, Mariana Sardinha, Lúcia Gil, Alexandra Montenegro, José Mendes, Leonor Fernandes, Patrícia Winckler, Ricardo Luz, Sónia Oliveira. Neoadjuvant trastuzumab and pertuzumab in combination with anthracyclines in HER2-positive early breast cancer: real-world data on effect of body mass index in cardiac safety [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-55.

Abstract OT3-01-01: A single-arm confirmatory study to evaluate the efficacy of non-surgical therapy for HER2 positive early breast cancer with clinical complete response after primary systemic therapy: (JCOG1806)

Abstract Background: The surgical treatment is the standard therapy for early breast cancer (EBC) after primary systemic therapy (PST). In more than half of HER2 positive (HER2(+)) breast cancer, pathological complete response (pCR) is achieved by PST with HER2 inhibitors and chemotherapy. However, non-surgical therapy is not an option for EBC with cCR after PST because of little evidence. We planned a single-arm confirmatory study to evaluate the efficacy and safety of the non-surgical therapy for HER2(+) EBC with cCR after PST. Methods: The key eligibility criteria are as follows: 1) Histologically confirmed as invasive ductal carcinoma of the breast, HER2(+). 2) cT1-2, N0, M0 (UICC 8th). 3) No ipsilateral BC. 4) Women aged 20-74 years. 5) ECOG performance status 0 or 1. 6) Adequate hematologic and organ function. 7) Ejection fraction as cardiac function is over 50%. 8) Written informed consent. HER2 inhibitors (trastuzumab and pertuzumab) and cytotoxic drugs as PST are administered to all patients (pts). After completion of PST, cCR is diagnosed by breast imaging and physical examination. cCR is defined as 1) Not palpable breast mass by physical examination, 2) No enhanced breast mass by enhanced MRI, and 3) No breast mass by ultrasonography. 4) For hormonal receptor (+) EBC, needle biopsy after PST must be done to evaluate the pCR. After a diagnosis of cCR, conventional radiotherapy for whole breast and boost radiation for tumor bed is mandatory, followed by pertuzumab and trastuzumab every 3 weeks for 9 months. In non-cCR cases, surgical resection is performed and adjuvant therapy is not specified. The primary endpoint is a distant metastasis-free survival (DMFS) at 3 years, the secondary endpoints are DFS, OS, RFS, the proportion of local recurrence, and cosmetics outcome. Given that the threshold and expected DMFS at 3-year is 93% and 98% with a significance level of 2.5% (one-sided) and 80% power, 170 cCR cases are required. Assuming half of the HER2 pts reach cCR, 350 pts are required as the sample size started PST. Enrollment launched in January 2020, and 260 pts are enrolled as of July 12, 2022. This clinical trial has been registered at the Japan Registry of Clinical Trials as jRCTs031190129 and conducted by the Japan Clinical Oncology Group (JCOG) Breast Cancer Study Group under a public fund (National Cancer Center Research and Development Fund). Citation Format: Tomomi Fujisawa, Hideo Shigematsu, Tadahiko Shien, Hiroji Iwata, Keita Sasaki, Taro Shibata. A single-arm confirmatory study to evaluate the efficacy of non-surgical therapy for HER2 positive early breast cancer with clinical complete response after primary systemic therapy: (JCOG1806) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-01-01.

Abstract PD18-03: Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer

Abstract BACKGROUND In the Phase II NeoSphere study (NCT00545688), dual HER2 blockade with pertuzumab (P) + trastuzumab (H), + docetaxel (D) significantly increased pathologic complete response (pCR) vs. H+D in the neoadjuvant setting for HER2-positive early breast cancer (EBC), locally advanced (LA) BC, or inflammatory BC, with supportive progression- and disease-free survival (DFS) data. Consistently, the randomized, multicenter, double-blind, placebo (Pla)-controlled Phase III PEONY trial (NCT02586025) significantly improved total pCR (tpCR; primary endpoint) with P+H+D vs. H+D in an Asian population, and safety data were in-line with the known P safety profile. We present the final analysis of long-term efficacy (at 3 and 5 years) and safety from the study. METHODS Patients had centrally confirmed HER2-positive EBC (T2–3, N0–1) or LABC (T2–3, N2 or N3; T4, any N) and were randomized 2:1 to four neoadjuvant P+H+D or Pla+H+D cycles every 3 weeks. P: 840 mg loading/420 mg maintenance doses (or Pla); H: 8 mg/kg loading/6 mg/kg maintenance; D: 75 mg/m2. Patients then received three fluorouracil, epirubicin, and cyclophosphamide cycles, followed by 13 of P+H or Pla+H in the adjuvant setting for up to 1 year. Long-term outcomes (event-free survival [EFS], DFS, overall survival [OS]; all secondary endpoints) were assessed by Kaplan–Meier methods, Cox proportional hazards models, and a two-sided log-rank test (stratified by disease category and hormone receptor status). RESULTS Data cut-off was Mar 14, 2022, and 329 patients were randomized; 219 to P; 110, to Pla. Safety populations were 218 and 110 patients, respectively. Baseline characteristics were well balanced. Most patients received the full HER2-targeted cycles. Median follow-up was 62.9 months. Long-term efficacy data are shown in the table. During the overall treatment period, 70.6% of patients in the P+H+D arm and 68.2% in the Pla+H+D arm experienced grade ≥3 adverse events (AEs); the most common (in ≥5% of patients in either arm) being neutropenia (59.2% vs. 55.5%), leukopenia (34.4% vs. 34.5%), and febrile neutropenia (5.0% vs. 3.6%). Of the most common any-grade AEs (in ≥30% of patients in either arm), diarrhea was more common in the P+H+D arm (40.8% vs. 17.3% in the Pla+H+D arm). Serious AEs were reported in 17.0% and 13.6% of patients, respectively. No primary cardiac events (heart failure [New York Heart Association grade III or IV] or significant decline of left ventricular ejection fraction) or secondary cardiac events occurred during any study periods. CONCLUSIONS Long-term efficacy endpoints (EFS, DFS, and OS) were supportive of the primary endpoint results (tpCR) and suggested a clinically meaningful improvement with P+H vs. Pla+H when administered before and after surgery for one year of anti-HER2- therapy. Safety data were in-line with the known P safety profile and generally comparable between arms, with the exception of diarrhea. PEONY adds to the totality of data showing the benefit of the P+H+D regimen in HER2-positive EBC. Table 1: Long-term efficacy data Citation Format: Zhi-Ming Shao, Da Pang, Hongjian Yang, Wei Li, Shusen Wang, Shude Cui, Ning Liao, Yong-Sheng Wang, Chuan Wang, Yuan-Ching Chang, Hwei-Chung Wang, Seok Yun Kang, Jae Hong Seo, Kunwei Shen, Suphawat Laohawiriyakamol, Zefei Jiang, Liang Huang, Haiyan Wang, François Lamour, Grace Song, Eleonora Restuccia. Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-03.

Abstract P1-11-11: HER2-directed therapy in early breast cancer – improvement over 20 years

Abstract Introduction: HER2-positive breast cancer is considered aggressive, but due to the development of targeted drugs in the past 20 years, a substantial improvement of therapy results can be postulated. Proven evidence is provided by data of randomized clinical trials. The present study aimed at demonstrating the improvement of therapy results over time using single-center real world data. Material and Methods: In our center, we prospectively built a consecutive tumor and data base from 2000 to 2020 and identified patients with early HER2-positive breast cancer (n=396). The cohort was divided in four groups by year of diagnosis according to the changing therapy concepts: A) 2000-2004 (no HER2-directed therapy, n=83), B) 2005-2011 (trastuzumab, n=96), C) 2012-2017 (trastuzumab/pertuzumab, n=135), D) 2018-2020 (T-DM1 in patients with non-pCR), n=55). HER2 was measured by IHC and ISH corresponding to the ASCO-CAP guidelines. HER2-directed therapy was indicated according to the respective national guidelines (AGO). The median follow-up was 58 months in the entire cohort (1-266), group A 84 months (10-266), group B 94 months (2-201), group C 56 months (1-118), group D 32 months (8-53). The primary endpoint was overall survival (OS), and secondary endpoint was iDFS. Kaplan-Meier estimates were calculated and multivariate analyses were performed using SPSS 28 (IBM, Armonk, NY, USA). Results: Overall, 57% of the 396 patients had an age of 50 years or more, 85% had a NST histology, 54% of the tumors were larger than 2cm, 45% were node-positive; 34% were steroid hormone receptor negative. HER2-directed therapy was delivered to 7 of 83 pts in group A (8.4%), to 62 of 96 pts in group B (64.6%), to 119 of 135 in group C (88.15%), and to 50 of 55 pts in group D (90.91%), resp.. Overall, in the first 3 years we observed 19 deaths and the probability for OS was 89.7 % for group A, 92.2 % for group B, 96.4 % for group C and 100% for group D, resp.; iDFS was 77.4% in A, 86.8% in B, 94.9% in C and 95.2% in D, resp.. After adjustment for nodal status, grading and steroid hormone receptor status, we calculated the effect size of the incremental improvement of treatment for OS and iDFS as HRs referred to group A (Table 1). Conclusion: With this prospectively established single center cohort, we are able to confirm a significant improvement of the treatment results in patients with HER2-positive early breast cancer over the last 20 years applying individualized HER2-directed therapies. Table 1. Multivariate analyses of OS and iDFS adjusted for nodal status, grading and hormone receptor status. Citation Format: Christoph Thomssen, Julia Engel, Kristin Reinhardt, Hans-Georg Strauß, Regina Große, Susanne Barrot, Marcus Bauer, Lisa van Uden, Sandy Kaufhold, Kathleen Schüler, Vanessa Wieder, Eva J. Kantelhardt, Martina Vetter. HER2-directed therapy in early breast cancer – improvement over 20 years [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-11.

Abstract P2-11-12: Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts

Abstract Background: All intrinsic molecular subtypes are represented among HER2-positive breast cancer, with implications on clinical outcome and treatment sensitivity. The impact of molecular subtypes on the pattern and site of relapse is largely unexplored. Methods: 677 patients with HER2-positive early breast cancer from the Shorther trial (n=437), the CherLOB trial (n=84) and two Institutional cohorts (Istituto Oncologico Veneto IRCCS Padova n=39 and Hospital Clinic Barcelona n=117) were included. Only patients with available PAM50 intrinsic molecular subtyping were considered. We analyzed the incidence of distant relapse (at any site and at specific sites) as the first event. Cumulative incidence was estimated according to competing risk analysis (Fine and Gray’s method). Competing risk regression was used to calculate the subdistribution Hazard Ratios (subHR) and their 95% Confidence Interval (CI). Results: The distribution of molecular subtypes was: 130 LumA (19%), 75 LumB (11%), 347 HER2-e (51%), 46 Basal (7%), 79 Normal (12%). Median follow up was 8.4 years (95%CI 8.2-8.6). The 10-yr cumulative incidence rates of distant relapse as first event were: LumA 7.9%, LumB 14.8%, HER2-e 14.7%, Basal 15.5%, Normal 10.4% (HER2-e vs LumA: SubHR 2.21, 95%CI 1.05-4.64, p=0.037). Table 1 shows the 5-yr and 10-yr cumulative incidence rates of distant metastases at specific sites (as first event) according to intrinsic subtype. HER2-e enriched and Basal tumors were more prone as compared to other subtypes to develop brain and lung metastasis as first event, respectively. Isolated brain metastases without extracranial disease occurred only in patients with HER2-e tumors. All brain metastases as first event occurred within 5 years from diagnosis. Bone-only disease as first event was less frequent in HER2-e and Basal subtype (subHR HER2-e vs LumA: 0.32, 95%CI 0.10-10.4. p=0.058). Next, we analyzed the frequency of site-specific first metastasis among patients who experienced a distant metastasis as first event (n=77). Lung metastases were more frequent in Basal tumors (LumA 25.0%, LumB 20.0%, HER2-e 24.4%, Basal 71.4%, Normal 0.0%, p=0.037) and bone metastases were more frequent in Luminal tumors (LumA 100.0%, LumB 60.0%, HER2-e 31.1%, Basal 42.9%, Normal 57.1%, p=0.006). Among 45 HER2-e patients with a first distant relapse, 25.6% were diagnosed with a brain metastasis and 15.6% had brain-only disease. Conclusions: Molecular subtypes influence the metastatic behaviour of clinically HER2-positive breast cancer. These results, if further validated, may have implication in planning personalized monitoring strategies. Table 1. 5-yr and 10-yr cumulative incidence rates of distant metastasis at specific sites (as first event) according to intrinsic subtype. Citation Format: Maria Vittoria Dieci, Giancarlo Bisagni, Stefania Bartolini, Antonio Frassoldati, Daniele Giulio Generali, Federico Piacentini, Gaia Griguolo, Enrico Tagliafico, Fara Brasó-Maristany, Nuria Chic, Francesca Porra, Roberto Vicini, Roberto D’Amico, Sara Balduzzi, Aleix Prat, PierFranco Conte, Valentina Guarneri. Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-12.

Abstract P2-01-04: Real-world clinical outcomes of patients with stage I HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab

Abstract Background: One year of adjuvant trastuzumab with 12 cycles of weekly paclitaxel represents the standard of care for patients with pathological tumor size ≤2cm, node-negative, HER2-positive early breast cancer. Data supporting this indication derive from a single-arm, phase II trial that enrolled 410 patients in the United States only, where the 3 years invasive disease-free survival (DFS) rate was 98.7% (95% CI 97.6-99.8). Therefore, real-world data regarding the clinical outcomes of these patients are needed to confirm the efficacy and safety of this adjuvant anthracycline-free regimen in this population. Methods: We conducted a retrospective, observational, multicentric study to investigate survival outcomes of patients with stage I HER2-positive early breast cancer treated with adjuvant paclitaxel and trastuzumab in seven selected sites in two countries (Belgium and Italy). Eligible patients were men and women with early breast cancer of pathological tumor size between 5 and 20 mm, node-negative (N0 or N1mic), and treated with weekly adjuvant paclitaxel for 12 weeks and trastuzumab (6 mg/kg every 3 weeks administration for 1 year). Patients with a history of previous cancers were not included. The primary endpoint was disease-free survival (DFS) at 3 years from diagnosis. Thus, an optimal follow-up of 3 years from surgery was required. Baseline clinico-pathological characteristics, treatment data, disease recurrences and survival status were extracted from medical records. Survival analysis was performed using log-rank regression test. Results: Overall, 240 patients who received their adjuvant treatment between January 2014 and December 2018 were included in the analysis. The median age was 59.5 years (IQR 50.0-66.9), and 69.6% of patients were post-menopausal at the time of diagnosis. Seventy (31.8%) patients had hypertension and 20 (8.3%) had other cardiac comorbidities. Ductal carcinoma was the most represented histological type (86.3%). The median tumor size was 12mm (IQR 9-15), only seven (2.9%) patients had N1miC, and the majority of tumors (85.0%) were ER-positive. Breast-conserving surgery was performed in 80.8% of patients and 78.2% of patients had adjuvant radiotherapy. The median number of administrated cycles of weekly paclitaxel was 12 (range 1-12) and for trastuzumab 18 (range 1-19). Only one patient stopped trastuzumab prematurely because of safety reason. Aromatase inhibitors were the most frequently administered endocrine therapy (75.7% of patients with ER-positive disease). With a median follow-up of 4.7 (IQR 3.6-5.6) years, we observed a 3-year DFS rate of 98.8% (95% CI 96.2-99.6), with only three disease recurrences (one local and two distant) and four deaths (none of which was breast cancer related) during the duration of the follow-up. Conclusions: In this real-world clinical outcome of patients with stage I HER2-positive breast cancer treated with adjuvant trastuzumab and paclitaxel appeared excellent, with a 1.2% rate of recurrence at 3 years. Our data support the efficacy of an anthracycline-free regimen in this population. A longer follow-up will provide more mature data on overall survival and late relapses, especially in the ER-positive subgroup of patients. Citation Format: Veronique Debien, Elisa Agostinetto, Marianna Sirico, Flavia Jacobs, Chiara Molinelli, Michel Moreau, Marianne Paesmans, Ugo De Giorgi, Armando Santoro, Donatienne Taylor, François P. Duhoux, Andrea Botticelli, Giacomo Barchiesi, Matteo Lambertini, Evandro de Azambuja, Martine Piccart. Real-world clinical outcomes of patients with stage I HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-01-04.

Abstract PD18-04: Prognostic implications of PIK3CA mutation by hormone receptor status and intrinsic subtype in early stage HER2-positive breast cancer: a correlative analysis from CALGB 40601

Abstract Background PIK3CA mutations have been described in 20-25% of early-stage HER2-positive breast tumors [1], and are associated with reduced pathologic complete response (pCR) rate after chemotherapy and anti-HER2 agents [2]. However, the independence of this finding and association with long-term outcomes within HER2+ patients is still largely unknown. Here, we studied the prognostic implications of PIK3CA mutations by hormone receptor (HR) status and intrinsic subtype in patients with early stage HER2+ breast cancer enrolled in CALGB 40601. Method In CALGB 40601, gene expression profiling by RNA sequencing (RNAseq) with PAM50-determined intrinsic subtype and PIK3CA mutations from whole exome sequencing (WES) were obtained from 184/305 (60%) pretreatment core biopsies. We examined the association of PIK3CA mutations with pCR and event free survival (EFS) by HR status and intrinsic subtype using logistic and Cox regression analyses. Results PIK3CA mutations were found in 32 patients (32/184, 17%). The most frequent mutation was H1047R (12/32,38%), followed by E545K (7/32,22%) and E542K (5/32,16%). PIK3CA mutations were present in 20% and 15% of HR-positive and HR-negative BC subpopulations, respectively. Within Luminal-B, Luminal-A and HER2-Enriched breast tumors, PIK3CA mutations occurred in 36%, 10% and 19% respectively. In the overall population there was lower rate of pCR in mutated-PIK3CA patients than wild-type (34% vs 49%). Using only the subset of patients treated with neoadjuvant trastuzumab-based therapy as standard of care (excluding the lapatinib plus paclitaxel arm), we found a statistically significant lower pCR rate among PIK3CA-mutated tumors using logistic regression model (30% vs 54%, OR=0.30, p=0.045). At a median follow-up of 9.1 years, the presence of PIK3CA mutation was significantly associated with worse EFS in the overall study population (HR 2.58, 95% CI 1.24- 5.35, p=0.011). In a multivariable model including pCR status, HR status and intrinsic subtype (HER2-E vs. not), PIK3CA mutation was independently and significantly associated with worse EFS (HR 2.18, 95% CI 1.04- 4.56, p=0.039). The negative impact of PIK3CA mutation on EFS was statistically significant only in patients with HR-positive (HR 3.6, 95% CI 1.45-8.96, p=0.06) and luminal breast tumors (HR 4.84, 95% CI 1.08-21.7, p=0.039), but not in HR-negative and non-luminal subtypes. Conclusion In our study, the presence of PIK3CA mutation was significantly associated with lower pCR rates in patients treated with chemotherapy plus trastuzumab. Moreover, in uni- and multivariable Cox models, PIK3CA mutations were associated with worse long-term survival, which appeared to be driven by HR-positive and luminal HER2-positive breast tumors.

Abstract P6-08-13: Home-based treatment with subcutaneous (SC) trastuzumab - only a pandemic solution? Real world evidence (RWE) analysis

Abstract Background The pandemic has accelerated the introduction of more flexible and cost-effective treatment forms. The efficacy of trastuzumab in the intravenous (IV) and SC forms is similar both in early and advanced HER2-positive breast cancer (BC) patients. Compared to IV administration, SC enables reduction of treatment costs and time, and saves equipment and human resources. SC formulation is more convenient for both patients and healthcare providers and may be implemented as a home-based therapy. Recently, systemic anticancer treatment (including chemotherapy) has been increasingly performed at home, improving patient comfort and reducing the burden on the healthcare system. Poland has already implemented home-based treatment with some biologic compounds; however, they have not included trastuzumab in BC patients. Objectives This RWE analysis aims to evaluate the organizational and therapeutic procedures related to the home-based treatment with SC trastuzumab and the attitudes of patients and healthcare providers to this approach. Material and methods The study enrolled early HER2(+) BC patients treated with trastuzumab during the COVID-19 pandemic. Monitoring and treatment duration were consistent with SmPC and reimbursement regulations in Poland. The first 3-6 doses of SC trastuzumab (alone or in combination with CHT) were administered at a cancer center in outpatient and inpatient settings. Subsequent doses were administered at home by 3 qualified breast nurses. Post-injection follow-up was used for educational purposes. Data were analyzed with descriptive statistics. The study was reviewed and approved by the local Bioethics Committee. Results The analysis included 20 patients treated in two comprehensive cancer centers in Poland with a median age of 59 years (range, 36-72 years). Seven patients (35%) were professionally active. The average distance from the place of residence to the cancer center was 24 km (range, 2-65 km). A total of 232 doses were administered (mean 11.6 doses per patient; range 6-14), 133 doses at home and 99 at the cancer center. The overall tolerance of trastuzumab was good and consistent with the known safety profile described in Summary of Product Characteristics. Only 1 patient (5%) discontinued treatment prematurely due to decreased LVEF; another 19 patients completed treatment as planned. For 19 patients (95%), the benefits of SC treatment included time savings, the ability to continue working, and avoiding crowded places and infection risk. 2 patients (10%) considered the nurse’s visit privacy disturbing, while 18 (90%) would recommend home-based drug administration. The average duration of a nurse’s stay at home was 60 minutes (range 30 to 130 minutes). No logistical or technical problems were reported, except for occasional patient lateness. Nurses positively assessed the treatment provided in the nursing office, which was a source of additional knowledge, and experience. The overall impression of home-based therapy was positive for both patients and nurses. The limitation of the study is the declarative nature of the data. Conclusions Home-based treatment with SC trastuzumab should be pursued due to its safety, ease of organization, positive perception by patients and nurses, and reducing healthcare system resources. It can be particularly valuable for disabled patients who have difficulty reaching the hospital and professionally active patients. Specialized, trained nurses can self-sufficiently carry out part of the prolonged trastuzumab treatment, reducing physician involvement. Citation Format: Barbara Radecka, Hudała-Klecha Joanna, Dariusz Sawka, Jolanta Sarga, Bożena Noworolska, Jolanta Sawicka, Elżbieta Duda, Natalia Obruśnik, Patryk Zając. Home-based treatment with subcutaneous (SC) trastuzumab - only a pandemic solution? Real world evidence (RWE) analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-13.

Abstract P2-16-04: MNX1 promotes tumor sensitivity to HER2-targeted therapy in HER2-positive breast cancer

Abstract Background: Female breast cancer has been the world’s leading cancer incidence among women. HER2-positive breast cancer accounts for about 15%~20% of all breast cancer, with a high degree of malignancy and easy metastasis and recurrence. With the development of medical technology and the continuous innovation of HER2 targeting drugs, patients with HER2-positive breast cancer have more treatment options and their prognosis had been greatly improved. However, there is still a lack of biomarkers for HER2-positive early breast cancer in clinical practice. Methods: This study prospectively collected single-center (Fudan University Shanghai Cancer Center, FUSCC) preoperative core needle biopsy samples of breast cancer patients from July 2017 to July 2018 who received neoadjuvant paclitaxel, carboplatin plus with trastuzumab (PCH). The patients were divided into pCR and non-PCR groups, and 81 patients were enrolled. The differential expression of genes was screened and validated by RNA-seq. The gene expression data for GSE181574 (this database has a total of 105 cases of breast cancer tissue samples were collected by core needle biopsy before neoadjuvant treatment. 52 cases underwent Ado-trastuzumab emtansine plus pertuzumab, 9 cases of paclitaxel plus trastuzumab, and 44 cases of paclitaxel plus trastuzumab and pertuzumab), GSE52707 (SK-BR-3 Lapatinib resistance cell group vs control group), and GSE15043 (BT474 Herceptin-resistant cell group vs control group), were downloaded from the Gene Expression Omnibus (GEO) database. Cell cloning formation, proliferation assay, and drug sensitivity experiments were conducted in MNX1 ectopic and knockdown cell lines. Co-IP assay, RNA-Seq, and ChIP-Seq analysis were used to explore the downstream pathways that MNX1 might be involved. Results: High-throughput sequencing results of core needle biopsy samples from 81 HER2-positive breast cancer patients were divided into pCR and non-pCR groups. Using DEseq2 packet analysis to screen differentially expressed genes, P-value < 0.05, | log2FoldChange | > 1 as the filter, there were 620 up-regulated genes and 715 down-regulated genes in the pCR group. The same method was used for the analysis of the GSE181574 data set. Combined the two datasets used P values and log2FoldChange (P-value < 0.05, | log2FoldChange | > 1.2) as selection criteria, we found the MNX1 and PNMT expressions were significantly higher in the pCR group. Subsequently, differential analysis of GSE52707 and GSE15043 datasets showed that MNX1 and PNMT expression levels were reduced in drug-resistant cell lines. Considering the P-value and | log2FoldChange |, we ultimately selected motor neuron and pancreatic homeobox 1(MNX1) gene as the target factors for follow-up studies. In the cloning formation and proliferation assay, overexpression of MNX1 inhibits proliferation and clonal formation of HER2-positive breast cancer cells. In the drug sensitivity experiments overexpression of MNX1 enhances the sensitivity of HER2-positive breast cancer cells to tyrosine kinase inhibitors (TKI) such as lapatinib and pyrotinib. MNX1 knockdown reduces the sensitivity of HER2-positive breast cancer cells to TKI. Through RNA-seq and ChIP-seq, we found that CD-M6PR might be a downstream target gene regulated by MNX1. Verification by Dual-Luciferase Reporter Assay MNX1 was found to positively regulate CD-M6PR transcription. By Co-IP assay, it was found that MNX1 interacted with EEF1D, and EEF1D stabilized MNX1. MNX1 and CD-M6PR affect the proliferation and drug sensitivity of breast cancer cells by down-regulating the PI3K-AKT-mTOR pathway. Conclusion: Overexpression of MNX1 increases the sensitivity of HER-2 positive cells to TKI. MNX1 binds to EEF1D and is stabilized by EEF1D. MNX1 positively regulates M6PR and affects the proliferation of breast cancer cells and the sensitivity of breast cancer cells to TKI through the PI3K-AKT-mTOR pathway. Citation Format: Wei-Ru Chi, Bingqiu Xiu, Min Xiong, Pei Li, Qi Zhang, Lun Li, Jianjing Hou, Xujie Zhou, Yuting Sang, Ming Chen, Liyi Zhang, Jingyan Xue, Yayun Chi, Jiong Wu. MNX1 promotes tumor sensitivity to HER2-targeted therapy in HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-04.

Abstract P1-11-18: The efficacy and safety of trastuzumab and pertuzumab in combination with different chemotherapy regimens for neoadjuvant treatment of HER2-posotive breast cancer: a multi-center real-world study in China

Abstract Background: Dual HER2 targeted therapy with trastuzumab (H) and pertuzumab (P) has been approved as neoadjuvant therapy for patients with HER2-positive breast cancer in China in 2019 based on the results from NeoSphere and PEONY study. However, the real-world efficacy and safety data are currently lack of evidence in China. Therefore, this multi-center real-world study aims to retrospectively analyze the efficacy and safety of neoadjuvant trastuzumab and pertuzumab combined with different chemotherapy regimens of HER2-positive early breast cancer. Methods: Patients received trastuzumab and pertuzumab in combination with different chemotherapy regimens, including taxanes (T), cyclophosphamide (C), anthracyclines (A) were collected retrospectively from 12 centers. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate. Results: A total of 357 patients were enrolled, among which 204 (57.5%) recieved TCbHP, 92 (25.9%) recieved EC-THP, and 51 (14.4%) received THP as chemotherapy regimens. The median age was 48 years old (range, 22-76), 142 (39.8%) of patients were classified as hormone receptor (HR)-positive, and 215 (60.2%) were HR-negative. The overall tpCR rate was 58.5% (95%CI, 53.2%-63.7%). tpCR rate for HR-negative patients was significantly higher than HR-positive patients (65.6% vs. 47.9%, p=0.001) and there was not any statistical difference according to chemotherapy regimens (56.9% for TCbHP, 56.5% for EC-THP, and 66.7% for THP, p=0.445). The most common adverse events included anemia (40.1%), white blood cell count decreased (34.3%), ejection fraction decreased (19.5%), Alanine aminotransferase increased (18.9%), platelet count decreased (12.8%) and neutrophil count decreased (12.0%). There was not any toxicity leading to death. Conclusions: Multi-center real-world data show satisfactory tpCR rate and tolerable adverse events of trastuzumab and pertuzumab in combination with different chemotherapy regimens in China. Citation Format: Xiaowei Qi, Hong Hu, chen wenlin, xu yan, liu shu, fang yanman, Taolang Li, ming jia, zhou sihai, chai fan, liang yueyang, fan yuanming, Yi Zhang, Peng Tang, jiang jun, nie jianyun, Li Chen, Shushu Wang. The efficacy and safety of trastuzumab and pertuzumab in combination with different chemotherapy regimens for neoadjuvant treatment of HER2-posotive breast cancer: a multi-center real-world study in China [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-18.

HER2 and BARD1 Polymorphisms in Early HER2-Positive Breast Cancer Patients: Relationship with Response to Neoadjuvant Anti-HER2 Treatment.

The addition to chemotherapy of anti-HER2 drugs such as trastuzumab or pertuzumab has improved outcomes in HER2-positive breast cancer patients. However, resistance to these drugs in some patients remains a major concern. This study examines the possible association between the response to neoadjuvant anti-HER2 treatment in breast cancer patients and the presence of 28 SNPs in 17 genes involved in different cell processes (PON1, CAT, GSTP1, FCGR3, ATM, PIK3CA, HER3, BARD1, LDB2, BRINP1, chr6 intergenic region, RAB22A, TRPC6, LINC01060, EGFR, ABCB1, and HER2). Tumor samples from 50 women with early breast cancer were genotyped using the iPlex®Gold chemistry and MassARRAY platform, and patients were classified as good responders (Miller-Payne tumor grades 4-5) and poor responders (Miller-Payne tumor grades 1-3), as assessed upon surgery after 6 months of treatment. Proportions of patients with the HER2Ala1170Pro (rs1058808) SNP double mutation were higher in good (58.62%) than poor (20%) responders (p = 0.025). Similarly, proportions of patients carrying the synonymous SNP rs2070096 (BARD1Thr351=) (wv + vv) were higher in patients showing a pathological complete response (46.67%) than in those not showing this response (15.15%) (p = 0.031). The SNPs rs1058808 (HER2Ala1170Pro) and rs2070096 (BARD1Thr351=) were identified here as potential biomarkers of a good response to anti-HER2 treatment.

Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial

Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P+ T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). Dual blockade with P+ T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.

Tumor biomarkers and efficacy in patients treated with trastuzumab emtansine + pertuzumab versus standard of care in HER2-positive early breast cancer: an open-label, phase III study (KRISTINE)

BackgroundKRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II–III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE.MethodsPatients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive.ResultsBiomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups.ConclusionsAlthough our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer.Trial Registration: ClinicalTrials.gov NCT02131064. Registered 06 May 2014.

Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study)

IntroductionTrastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. Material and methodsWe conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. ResultsA total of 114 patients were included (March–July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1–3 N0–1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. ConclusionThe KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data.

Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer.

The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment.

Antibody-drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these 'off-target effects', such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment.

Baseline Troponin Level and Cardiac Toxicity in HER2-positive Early Breast Cancer Patients Receiving Trastuzumab.

There is controversy around the use of high-sensitive troponin T (hs-TnT) as an early biomarker of cardiac toxicity in patients with breast cancer on trastuzumab (T). Patients receiving adjuvant or neo-adjuvant T for early HER2-positive breast cancer were prospectively included. Transthoracic echocardiograms and matched hs-TnT before T and at 3, 6, and 9 months were performed on all patients. Congestive heart failure, cardiac death, a decline in left ventricular ejection fraction (LVEF) of more than 10% from baseline even if it is still within the normal range, or a drop in LVEF below 55% were all considered signs of cardiac toxicity. In total, 24 patients (median age: 57; range=39-79 years) were enrolled. Anthracyclines were administered to all patients but three as part of neo/adjuvant treatment before T. Cardiovascular toxicity was observed in 3 out of 24 (12.5%) patients: two non-symptomatic LVEF declines (8.3%) and one heart failure episode (4.2%). In the entire population, the mean baseline hs-TnT level was 10.1±8.8 pg/ml, and after 3, 6, and 12 months, no appreciable change was observed. Patients with cardiac toxicity had mean hs-TnT levels higher than those without (18.3±12.3 vs. 8.2±7.2 pg/ml; p=0.049). A definite trend was evident in the chi-square test (chi2=3.52; p=0.06). In anthracycline-exposed patients with early breast cancer, hs-TnT may be able to identify those at risk of developing cardiac toxicity during neo/adjuvant T treatment.