Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib

Abstract

Purpose Dual human epidermal growth factor receptor 2 (HER2) targeting can increase pathologic complete response rates (pCRs) to neoadjuvant therapy and improve progression-free survival in metastatic disease. CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel, considering tumor and microenvironment molecular features. Patients and Methods Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. An investigational arm of paclitaxel plus lapatinib (TL) was closed early. The primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression–based assays. Results Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor–positive subset but a significant increase in pCR with dual therapy in those with hormone receptor–negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P < .001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%). Conclusion pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.

Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth

“…Our enzymatic and cellular assays indicated that the potential for such activities based on ITK and BTK inhibition were relatively unique for ibrutinib compared with other ERBB kinase family inhibitors studied. Recent clinical results have highlighted the potential importance of immune mechanisms in limiting efficacy of current HER2-targeting agents (34,35).…”

Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

“…Significant genetic heterogeneity exists both within a single primary breast cancer (1)(2)(3) and across patients (4)(5)(6)(7). Despite this intratumor heterogeneity, the intrinsic gene expression features of the primary tumor as measured by RNA can predict future sites of recurrence (8,9), response to therapy (10), and overall survival (8,11). Few studies have compared both the RNA and DNA sequencing of multiple distant metastases within a patient, or across multiple subtypes of breast cancer from larger cohorts of patients.…”

Diverse biology of breast cancer: search for adequate treatment

“…Гетерогенность ответа на HER2 -таргетную терапию свя-зывается с биологическим подтипом, гормонально-рецеп-торным статусом, изменениями в сигнальных патогене-тических путях, таких как фосфатидилинозитол 3-киназа (РI3К), а также с противоопухолевыми иммунными отве-тами [24,25]. Геномный анализ HER2 позитивных опухолей (по ИГХ) с оценкой профилей генной экспрессии выявил шесть подтипов РМЖ: базально-подобный, люминальный А, лю-минальный В, НЕR2-обогащенный [HER2E], низкоклауди-новый и нормально-подобный [26]. Другие сигнатуры генной экспрессии, имеющие отноше-ние к HER2 сигнальному пути и ответу на терапию были также протестированы и включали гены пролиферации, РI3К -путь и 5 сигнатур инфильтрации иммунными клет-ками (иммуноглобулин G [IgG], В-клетки, Т-клетки, СD8+ и др.…”

“…В исследовании Carey и соавт. [26] [31] показали, что пациенты с ER-негативными опухолями чаще достигают полный регресс (pCR), чем пациенты с гормон-рецептор позитивными опухолями после одной анти-HER2 терапии или ее комбинации с химиотерапией. Это, конечно, не исключает потенциальную пользу тра-стузумаба и при ER-позитивных опухолях.…”