Abstract P5-13-24: Efficacy of first line CDK4/6 inhibitors in HER2-low vs HER2-zero, hormone receptor positive, HER2 negative metastatic breast cancer

Abstract

Introduction: CDK4/6 inhibitors are the standard of care in the vast majority of patients with metastatic breast cancer (MBC) in first line setting. HER2-low expression, defined as IHC score of 1+ or 2+ with negative ISH assay, has been associated with resistance to CDK4/6 inhibitors. This has not yet been explored for advanced disease in the first line setting. We aimed to analyze the efficacy of CDK4/6 inhibitors in this subset of patients compared to HER2-zero tumors. Methods: We identified patients with positive hormone receptors and HER2 negative metastatic breast cancer treated with first line CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) and letrozole or fulvestrant between December 2017 - April 2021 in our institution (Hospital 12 de Octubre, Madrid, Spain). HER2 expression and PAM50 subtypes were analyzed in metastatic tissue samples for all patients. For the analysis, patients were classified as HER2-zero or HER2-low groups. Our main objective was to evaluate the relationship between HER2 expression and progression-free survival (PFS) with log-rank test. Multivariable Cox regression model was used to estimate the adjusted hazard ratio (HR). As secondary objectives, we analyzed this association in all CDK4/6 subgroups and described the prevalence of PAM-50 subtypes in each category (HER2-low and HER2-zero). Results: We included 82 patients in our final analysis. 57% of the patients were classified in the HER2-low category. In our sample, 49% of patients received palbociclib, 39% ribociclib and 12% abemaciclib. A high proportion of patients presented visceral disease (75% in the HER2-zero vs 60% in the HER2-low group). Only 20% of tumors were considered as hormone-resistant. The overall response rate was slightly higher in the HER2-zero category (41% vs 35% in the HER2-low). With a median follow-up of 14 months (2 - 48 months), the median PFS was 31.7 months (95%CI: 20.3 - NR months) in the HER2-zero category and 22.8 months (95%CI: 15.7 - NR months) in the HER2-low (p=0.37). In the multivariable Cox regression model, HER2-low tumors were associated with a non-significantly higher risk of progression (HR=1.62; CI 95%:0.74-3.54). In patients treated with palbociclib, the median PFS for HER2-zero vs HER2-low categories were 31.7 months and NR (p=0.79), respectively. For ribociclib, the HER2-zero had a median PFS of 38.4 months and 33.1 months in the HER2-low category (p=0.47). In patients treated with abemaciclib, median PFS was NR for HER2-zero group and 9.2 months for HER2-low (p=0.18). The interaction test between HER2 categories and CDK4/6 inhibitors was not statistically significant (p=0.48). PAM-50 subtypes information was available for 47 patients. In these patients the prevalence of PAM-50 subtypes showed a relative higher proportion of luminal subtypes in the HER2-zero category (95%) and non-luminal (HER2-enriched and normal-like subtypes) in the HER2-low category (21%). Conclusions: In our sample, HER2-low category had a shorter median PFS in first line treatment with CDK4/6 inhibitors plus endocrine treatment compared to HER2-zero group. This finding was consistent for the three CDK4/6 inhibitors analyzed, although the HER2-low group showed more relative benefit in terms of PFS with palbociclib. Our results suggest a lower benefit of CDK4/6 inhibitors in the first line treatment of HER2-low MBC, which could be partially explained by a relative higher proportion of non-luminal PAM-50 subtypes in HER2-low tumors. FundingThis project has received a research grant from “Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad” (Spain) awarded within the National Research Program with reference PI 18/01408, co-funded with European Union ERDF funds (European Regional Development Fund). Citation Format: Rodrigo Sanchez-Bayona, Santiago Terán, Ana Sánchez De Torre, Manuel Alva, Laura Lema, Luis Manso, Estefanía Toledo, Ana Maria Roncero, Cristina Merino, Mario Martínez, Lucía Parrilla, Eva Ciruelos, Pablo Tolosa. Efficacy of first line CDK4/6 inhibitors in HER2-low vs HER2-zero, hormone receptor positive, HER2 negative metastatic 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 P5-13-24.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors

“…Previous studies suggested an association between HER2-low status and worse PFS in HR + /HER2-negative aBC patients receiving ET + CDK4/6i [3][4][5] . However, these studies were limited by small sample size 4,5 , lack of statistically significant results 5 , or inclusion of patients treated with ET + CDK4/6i as any line of therapy 3,5 .…”

“…Previous studies suggested an association between HER2-low status and worse PFS in HR + /HER2-negative aBC patients receiving ET + CDK4/6i [3][4][5] . However, these studies were limited by small sample size 4,5 , lack of statistically significant results 5 , or inclusion of patients treated with ET + CDK4/6i as any line of therapy 3,5 . While our findings confirm and expand results of these studies in a larger cohort of patients receiving first-line CDK4/6i, they also provide first evidence that HER2-low status is associated with worse patient OS, which is unlikely to be attributable to the number of subsequent lines of therapy; indeed, in our study patients with HER2-low disease received a higher average number of subsequent lines of systemic therapy when compared to patients with HER2-0 disease after tumor progression to ET + CDK4/6 inhibitors.…”

“…HER2-low BC has been recently proposed as a distinct biological and clinical BC entity 1 . However, preclinical and clinical evidence supporting this notion is still poor, also due to conflicting results of clinical studies published so far [2][3][4][5][6][7][8][9] , and which may in part derive from the fact that the prognostic significance of HER2 status has been evaluated in heterogeneous clinical contexts, including patients with different tumor stages, or treated with different types of therapies.…”

“…The combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is the standard-of-care, first-line therapy for the vast majority of HR + /HER2-negative aBC patients 11 . However, with the exception of a few small studies [3][4][5][6][7][8][9] , the prognostic impact of HER2 status (i.e., low vs. 0) in HR + /HER2-negative aBC patients treated with ET + CDK4/6i remains unclear. Here, we conducted a multicentric study to investigate the association between HER2 status (low vs. 0) and the PFS or OS of HR + /HER2-aBC patients treated with first-line ET + CDK4/6i.…”

Survival Outcomes in Patients With Hormone Receptor–Positive Metastatic Breast Cancer With Low or No ERBB2 Expression Treated With Targeted Therapies Plus Endocrine Therapy

“…Two previous studies have found that low ERBB2 expression is associated with a poor prognosis in patients with HR-positive mBC treated with CDK4/6is when compared with those who have no ERBB2 expression by immunohistochemical analysis. 12,14 Two other contemporaneous studies showed that low ERBB2 expression did not affect the response to CDK4/6is. 15,16 More data are needed to better understand whether low ERBB2 expression is truly prognostic and whether it merits consideration as a distinct entity, especially in HR-positive mBC, given the contradicting information.…”