Abstract P2-09-12: Independent validation of the HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer

Abstract

Background: HER2-positive breast cancer consists of 4 intrinsic molecular subtypes (Luminal A, Luminal B, HER2-enriched [HER2-E], and Basal-like) and a Normal-like subtype, with the HER2-E subtype having the highest activation of the EGFR-HER2 pathway. Concordant with this, the HER2-E subtype was significantly associated with pathological complete response (pCR) following lapatinib and trastuzumab without chemotherapy on the PAMELA phase II neoadjuvant trial (Lancet Oncol 2017). Here, we aimed to further validate this observation in a different cohort using tumor samples from the TBCRC023 trial. Methods: TBCRC023 (NCT00999804) was a randomized phase II trial combining a Simon Phase 2 design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Ninety-seven women with HER2+ breast cancer measuring 2 cm or larger (median = 5 cm) were randomized in a 1:2 ratio to 12 vs. 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was added in patients whose tumors were also estrogen receptor (ER)-positive. All evaluable patients were assessed for pCR, defined as no residual invasive carcinoma in the breast. Intrinsic molecular subtypes from tumor biopsy formalin-fixed, paraffin-embedded samples taken at baseline (day 0) were determined with the nCounter-based PAM50 predictor. Gene expression PAM50 data was performed at Hospital Clínic in Barcelona blinded from clinical data. The primary outcome was the association of the HER2-E subtype (vs. non-HER2-E) with pCR. A logistic regression model adjusted for tumor size, ER status, nodal status and treatment arm was performed. Results: A total of 85 of the 97 (87.6%) baseline tumor samples were available. Most patients had the HER2-E subtype (51 [60.0%]), followed by Normal-like (12 [14.1%]), Basal-like (11 [13.0%]), Luminal B (7 [8.2%]) and Luminal A (4 [4.7%]). The proportion of patients with HER2-E tumors within ER+ and ER-negative disease was 54.9% and 67.7%, respectively. At the time of surgery, 17 of 85 patients (20.0%; 95% confidence interval [CI] 0.13-0.30) had a pCR in the breast. Fourteen of 51 patients with the HER2-E subtype (27.5%; 95% CI 0.17 to 0.41) and 3 of 34 patients with non-HER2-E subtypes (8.8%; 95% CI 0.03 to 0.23) achieved a pCR at the time of surgery (adjusted odds ratio 4.33; 95% CI 1.08-17.41; P=0.039). No other clinical-pathological variable was found significantly associated with pCR in the multivariable model. Conclusions: In an independent validation study performed while blinded to clinical outcomes, HER2-E subtype confirms its ability to identify patients with HER2-positive breast cancer who are likely to benefit from dual HER2 blockade therapies without chemotherapy. Further studies should be performed to prospectively validate this biomarker, alone or in combination with other biomarkers. Citation Format: Prat A, De Angelis C, Pascual T, Gutierrez C, Wang T, Paré L, Rexer B, Cortes J, Forero A, Llombart A, Wolff AC, Krop I, Galván P, Pavlick AC, Villagrasa P, Hilsenbeck SG, Schiff R, Osborne CK, Rimawi MF. Independent validation of the HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-12.

Meta-Analysis of HER2-Enriched Subtype Predicting the Pathological Complete Response Within HER2-Positive Breast Cancer in Patients Who Received Neoadjuvant Treatment

“…A total of 506 relevant articles were identified in a primary literature search (Supplementary Figure 1). After exclusion of duplicate references and those that did not satisfy the inclusion criteria, 15 candidate articles were included in the meta-analysis (8,(10)(11)(12)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Three studies were published only in abstract form (26,28,29).…”

“…After exclusion of duplicate references and those that did not satisfy the inclusion criteria, 15 candidate articles were included in the meta-analysis (8,(10)(11)(12)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Three studies were published only in abstract form (26,28,29). All features of the eligible studies in the metaanalysis were summarized in Table 1.…”

“…Seven studies defined pCR as having no residual invasive cancer cells within surgical specimens of both the primary tumor and axillary lymph node and allowed for ductal carcinoma in situ (DCIS) (ypT0/isypN0) (11,12,20,(23)(24)(25)28), while the other eight studies defined pCR as a lack of residual invasive cancer cells within surgical specimens of primary tumors regardless of axilla and allowed for DCIS (ypT0/is) (8,10,21,22,26,27,29).…”

“…Ten studies or subgroups included 716 patients of the HER2enriched and 524 of the non-HER2-enriched subgroups, with 428 and 157 patients exhibiting pCR, respectively (8,20,22,23,25,(27)(28)(29). Five studies administered neoadjuvant trastuzumab plus lapatinib (8,22,23,27,29), four used neoadjuvant trastuzumab plus pertuzumab (20,25,28), and one used neoadjuvant pertuzumab plus T-DM1 as HER2-targeted therapy (28). The majority of chemotherapy regimens included anthracyclines and/or taxanes.…”

Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer

“…Importantly, HR status lost its association with pCR once intrinsic subtype was taken into account in a multivariable model. A subsequent validation of the predictive value of the HER2-E subtype in 85 samples from the TBCRC023 [65] trial has recently been reported. Overall, these data suggest that HER2-E subtype is a predictor of anti-HER2 sensitivity, and could help identify in the future a group of patients with HER2+ early BC that might be cured with anti-HER2 treatment without chemotherapy, or a group of patients with HER2+ advanced or metastatic disease that can be treated with dual HER2 blockade-only.…”