How I treat HER2-low advanced breast cancer

 

by Ilana Schlam, Sara M. Tolaney, Paolo Tarantino 

 

The Breast: Published: January 11, 2023

 

Introduction

Targeting low levels of human receptor epidermal growth factor 2 (HER2) expression has reshaped the treatment paradigm for half of the patients with advanced breast cancer. HER2-low is currently defined as a HER2 immunohistochemical expression of 1+ or 2+ without amplification by in-situ hybridization. Until recently, HER2-targeted agents were ineffective in treating patients with HER2-low disease.

Areas covered

In this narrative review, we summarize the current management of HER2-low breast cancer. We highlight the findings of the DESTINY-Breast 04 phase 3 trial, which confirmed the efficacy of trastuzumab-deruxtecan (T-DXd) for the treatment of patients with advanced, pretreated HER2-low breast cancer. We also discuss how to implement this new treatment option in treatment algorithms of hormone receptor (HR)-positive and triple-negative tumors, as well as how to optimally manage selected toxicities of T-DXd.

Expert opinion

T-DXd is currently the standard of care for patients with advanced, pretreated, HER2-low breast cancer. Based on the design of the DESTINY-Breast04 trial, the current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer. Up to 10–15% of the patients receiving T-DXd are expected to develop interstitial lung disease, which in 1–2% of the cases can be fatal. Adequate monitoring and prompt management are required to minimize the impact of ILD and to safely implement T-DXd in clinical practice.

 

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial

 

by Stephen R D Johnston, Masakazu Toi, Joyce O'Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun-Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara M Tolaney, Matthew P Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valérie André, Nadia Harbeck, Miguel Martin, monarchE Committee Members 

 

The Lancet Oncology: VOLUME 24, ISSUE 1, P77-90, JANUARY 2023

 

Background

Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up.

Methods

In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing.

Findings

Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37–47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578–0·762, nominal p<0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2–87·3] in the abemaciclib plus endocrine therapy group vs 79·4% [77·5–81·1] in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748–1·153; p=0·50). The most common grade 3–4 adverse events were neutropenia (in 548 [19·6%] of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of 2800 patients in the endocrine therapy alone group), leukopenia (318 [11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six [0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group.

Interpretation

Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients.

 

 

 

Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: A propensity score-adjusted analysis of a prospective cohort study

 

by RESPECT study group 

The Breast: VOLUME 66, P245-254, DECEMBER 01, 2022

Purpose

To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT).

Methods

Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed.

Results

We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing HRQoL deterioration at 36 months (P = 0.717).

Conclusion

Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Trastuzumab monotherapy could be considered for older patients who reject chemotherapy.

 

Antibody drug conjugates targeting HER2: Clinical development in metastatic breast cancer

 

by Elie Rassy, Layal Rached, Barbara Pistilli 

 

The Breast: VOLUME 66, P217-226, DECEMBER 01, 2022

 

The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb) such as trastuzumab and pertuzumab, which led to dramatic improvements in survival outcomes. Lately, the great strides made toward developing antibody-conjugation methods have led to the development of a new class of compelling compounds, the antibody-drug conjugates (ADCs) targeting HER2 which have profoundly transformed the treatment landscape of breast cancer. HER2-targeting ADCs, trastuzumab-emtansine and trastuzumab-deruxtecan, have improved the overall survival in the second and third-line settings with manageable adverse events. Other HER2-targeting ADCs using novel technological advances in the antibody, linker and/or payload conception have shown promising activity in preclinical and clinical studies and some of them are now being evaluated in larger clinical trials. Multiple challenges still impede the success of ADCs in breast cancer namely the lack of a comprehensive understanding of resistance mechanisms as well as the mechanisms of action of ADCs in special subgroups of patients such as those with low or ultra-low HER2 expression and patients with brain or leptomeningeal metastases (BM). In this framework, we review the approved indications and ongoing trials for HER2-targeting ADCs, across patient subgroups, including those with BM and discuss the associated potential mechanisms of action and resistance. Last, we provide an overview of the future perspectives involving HER2-targeting ADCs in breast cancer.

Breast Surgery Bulletin: July 2022

 

Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer

 

by A. Viansone, B. Pellegrino, C. Omarini, M. Pistelli, D. Boggiani, A. Sikokis, V. Uliana, D. Zanoni, C. Tommasi, B. Bortesi, F. Bonatti, F. Piacentini, L. Cortesi, R. Camisa, P. Sgargi, M. Michiara, A. Musolino 

 

The Breast: Published: July 31, 2022

 

Background

HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients.

Materials and methods

Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status.

Results

One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3–16.7).

Conclusions

Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

 

Current challenges and unmet needs in treating patients with human epidermal growth factor receptor 2-positive advanced breast cancer

 

by Matti Aapro, Fatima Cardoso, Giuseppe Curigliano, Alexandru Eniu, Joseph Gligorov, Nadia Harbeck, Andreas Mueller, Olivia Pagani, Shani Paluch-Shimon, Elzbieta Senkus, Beat Thürlimann, Khalil Zaman 

 

The Breast: Published: July 30, 2022

 

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed.

 

Treatment and outcomes of older versus younger women with HER2-positive metastatic breast cancer in the real-world national ESME database

 

tby Annonay Mylène, Gauquelin Lisa, Geiss Romain, Ung Mony, Cristol-Dalstein Laurence, Mouret-Reynier Marie-Ange, Goncalves Anthony, Abadie-Lacourtoisie Sophie, Francois Eric, Perrin Christophe, Le Fel Johan, Lorgis Véronique, Servent Véronique, Uwer Lionel, Jouannaud Christelle, Leheurteur Marianne, Joly Florence, Campion Loic, Courtinard Coralie, Villacroux Olivier, Petit Thierry, Soubeyran Pierre, Terret Catherine, Bellera Carine, Brain Etienne, Delaloge Suzette 

 

The Breast: VOLUME 60, P138-146, DECEMBER 01, 2021

 

 Background

Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes according to age.

Methods

Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70).

Results

Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1–52.4), 35.3 (95% CI, 31.5–37.0) and 54.2 months (95% CI, 50.8–55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3–13.3), 11.1 (95% CI, 10.0–12.3) and 13.2 months (95% CI, 12.7–13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 [95% CI: 2.05–3.79]; endocrine therapy and/or anti-HER2 1.96 [95% CI: 1.43–2.69]).

Conclusions

In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out.

Anti-HER2 antibody prolongs overall survival disproportionally more than progression-free survival in HER2-Positive metastatic breast cancer patients

 

Anti-HER2 antibody prolongs overall survival disproportionally more than progression-free survival in HER2-Positive metastatic breast cancer patients

 

by I-Chun Chen, Fu-Chang Hu, Ching-Hung Lin, Shu-Min Huang, Dwan-Ying Chang, Ann-Lii Cheng, Yen-Shen Lu 

 

The Breast:  VOLUME 59, P211-220, OCTOBER 01, 2021

 

Background

This meta-analysis aimed to test the hypothesis that the HER2-positive metastatic breast cancer (mBC) patients treated with anti-HER2 antibodies in trial intervention arms have a greater prolongation of overall survival (OS) than of progression-free survival (PFS) and this extra-prolongation of median survival time in OS relates specifically to the anti-HER2 antibody.

Methods

The NCBI/Pubmed and Cochrane databases were searched systematically for HER2-positive or mBC trials published in English during January 1999–November 2017. Treatment arms with shorter PFS were considered as the “control” arm, whereas those with longer PFS as the “test” arm. The between-treatment drug differences were grouped into nine categories. Groups with or without anti-HER2 antibodies were pooled respectively for comparisons. The interrelationships between PFS and OS hazard ratios (HRs) and median survival time differences were investigated by conducting fixed-effects and mixed-effects linear meta-regression analyses.

Results

Twenty-eight trials (10,928 patients) from 438 articles were collected, and four with missing data were excluded in meta-regression analysis. Overall median PFS (HR = 0.73, 95% CI: 0.68–0.78) and median OS (HR = 0.82, 95% CI: 0.77–0.87) weakly favored the longer PFS arm with a weak correlation between the PFS and OS HRs. However, the between-treatment drug difference was anti-HER2 antibody, the absolute increment in median OS time was double that of median PFS time (p < 0.001) and linearly correlated, which was not found with any non-anti-HER2 antibody drug differences.

Conclusions

Anti-HER2 antibody in patients with HER2-positive mBC prolonged OS more than PFS and mandates further investigation.