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.
Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare tumors composed of two different histological components, one of which is of a neuroendocrine origin. Given its suggested underdiagnosis and consequent low prevalence, no clear diagnostic and treatment guidelines are available, and treatment usually follows regimens similar to that of the most aggressive component. On the other hand, multiple primary tumors (MPTs) are also rare neoplastic entities that usually confer a challenge regarding treatment options, for a regimen that comprises both the primary and the synchronous/metachronous malignancy should be used. Here, we discuss the challenging diagnostic and therapeutic management of a patient with an ileocecal MiNEN that presented along with a synchronous squamous non-small-cell lung cancer (SQ-NSCLC). The patient presented with intestinal obstruction symptoms for which he underwent an emergency resection of the ileocecal MiNEN. An initial CT scan showed an additional lung mass later identified as an SQ-NSCLC after bronchoscopy biopsy analysis. Given the rapid hepatic metastatic progression, palliative platinum-based chemotherapy was initiated, with an adequate response of the local and metastatic lesions of the MiNEN, but suggested platinum resistance and progression of the pulmonary neoplasm. Second-line treatment with pembrolizumab directed for the SQ-NSCLC was initiated; however, it was stopped after immune-mediated toxicities developed. A third-line chemotherapy scheme with carboplatin/gemcitabine was initiated, but central nervous system (CNS) progression developed, with the patient dying 11 months after initial diagnosis.
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