Breast Cancer Heterogeneity Confounds Trial of Dual HER2-Targeted Therapy

Lisa A. Carey, MD

Dual HER2-targeted neoadjuvant therapy for early breast cancer did not significantly improve pathologic complete response (pCR) rate as compared with a single anti-HER2 agent plus chemotherapy, according to results from the phase III CALGB 40601 trial.¹ Further, exploratory analyses of response by tumor intrinsic subtype revealed considerable heterogeneity, including in response to therapy. The data were presented at the 2013 ASCO Annual Meeting.

In CALGB 40601, the combination of paclitaxel, trastuzumab (Herceptin), and lapatinib (Tykerb) led to pCR in 56% of patients versus 46% with paclitaxel and trastuzumab. The 10-point absolute difference did not meet the prespecified improvement required for statistical significance, primarily because the paclitaxel/trastuzumab combination achieved a higher-than-expected pCR rate.

“The addition of lapatinib to 16 weeks of paclitaxel/ trastuzumab did not meet predefined criteria for a significant increase in pCR,” said Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill (UNC), who presented the data at the ASCO meeting. “Higher pCR rates were noted among hormone receptor-negative than hormone-positive tumors, as has been seen in other studies.

“Exploratory analyses by intrinsic subtype showed that HER2-positive breast cancer is molecularly heterogeneous. Intrinsic subtypes appear to differ in sensitivity to HER2-targeting agents, with the numerically highest pCR rates among the HER2- enriched subtype.”

The rationale for CALGB 40601 came from earlier trials showing an improved pCR rate in patients with metastatic HER2-positive breast cancer previously treated with two anti-HER2 agents. Carey said the trial was designed to provide additional quantitative information about pCR following neoadjuvant therapy with two versus one HER2-targeted therapies.

Investigators randomized 305 patients with stage II-III HER2-positive breast cancer to weekly paclitaxel plus trastuzumab, lapatinib, or both. Neoadjuvant therapy continued for 16 weeks, and the primary objective was pCR. The trial design had the statistical power to demonstrate an improvement in pCR from 30% with paclitaxel/trastuzumab to 50% with the three-drug regimen.

Accrual to the paclitaxel/lapatinib arm ended prematurely when a preliminary analysis of a similar ongoing trial revealed unfavorable efficacy and toxicity data, said Carey.

The lapatinib-containing regimens had more grade ≥3 toxicity, including neutropenia, rash, and diarrhea.

The response data showed pCR rates of 56% with the three-drug regimen versus 46% with paclitaxel plus trastuzumab. The paclitaxel/lapatinib arm had a pCR rate of 37% among women who had completed therapy prior to discontinuation of the arm.

About 60% of patients had hormone receptor— positive breast cancer, and a preplanned analysis showed that all three regimens resulted in higher pCR rates among women with hormone receptor– negative cancers—77% with the three drugs, 55% with paclitaxel/trastuzumab, and 37% with paclitaxel/ lapatinib versus 42%, 39%, and 31%, respectively, in hormone receptor–positive breast cancer.

Putting the results into context, Carey noted that CALGB 40601 and three other randomized trials of neoadjuvant therapy in HER2-positive breast cancer had consistently demonstrated numerically higher pCR rates with dual anti-HER2 therapy. In two of the trials (NeoSPHERE and NeoALTTO), the difference in favor of dual anti-HER2 therapy reached statistical significance.

Though consistent, the primary results of the four trials showed substantial heterogeneity in terms of pCR rates. The trials employed different chemotherapy regimens, and the length of neoadjuvant treatment varied somewhat. Even so, underlying differences in the patient populations might have played a role in the results, said Carey.

In an embedded correlational study, CALGB 40601, investigators compared pCR rates by breast cancer intrinsic subtypes. Pretreatment analysis of 160 patients showed that a third of the tumors were HER2-enriched, another third were luminal A, and more than 20% were luminal B. Normal-like (8%) and basal-like (7%) tumors accounted for the remainder.

Posttreatment analysis of 63 patients showed residual disease consisted of <5% in luminal B and basal-like tumors, 6% in HER2-enriched, 29% in luminal A, and 57% in normal-like tumors.

Analysis of instrinsic subtypes of hormone receptor status also showed considerable variability. HER2-enriched subtype predominated in hormone receptor-negative tumors (52%), whereas luminal A accounted for 43% of hormone-receptor positive tumors, luminal B for 34%, and HER2-enriched for 18%.

pCR and Breast-Conserving Surgery

An analysis of pCR by intrinsic subtype revealed additional evidence of variability, and 75% of HER2-enriched tumors had pCR versus 35% of luminal A tumors and 29% of luminal B tumors. Though patient numbers dwindled with each subgroup analysis, Carey showed that intrinsic subtype also influenced pCR by treatment regimen, reaching 80% to 90% in HER2-enriched tumors treated with either of the trastuzumab-containing regimens.CALGB 40601 included several surgical analyses, one of which focused on the relationship between pCR and breast-conserving surgery. Treating surgeons assessed each patient’s candidacy for breast preservation before and after neoadjuvant chemotherapy, said David W. Ollila, MD, a general surgical oncologist at UNC.²

The study population included 292 patients who could be evaluated for breast conservation. Of those, 123 (42%) were considered candidates by their surgeons and 169 (58%) were not. Following neoadjuvant therapy, 116 (94%) patients who were candidates for breast conservation before therapy remained candidates. In the group of patients whose cancers were initially considered unsuitable for breast conservation, 72 (43%) converted to breast-conservation candidacy after neoadjuvant therapy.

Subsequently, surgeons attempted breast conservation in 92 of 116 patients (79%) who were considered candidates before neoadjuvant therapy and in 51 of 72 patients (71%) who converted to breast-conservation status after treatment. Using tumor-free margin status to define successful breast conservation, 74 of 92 (80%) and 39 of 54 (76%) of the two groups of candidates had successful breast-conserving surgery.

“If the surgeon chooses properly, we have a four out of five chance of achieving tumor-free surgical margins and achieving breast preservation,” said Ollila.

The analysis showed that pCR did not correlate significantly with any of the subgroups, as pCRs occurred in patients who were initially considered candidates for breast conservation, those who converted to breast conservation, and patients who ultimately were decided to be unsuitable for breast conservation.

1. Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol. 2013;31(suppl; abstr 500).
2. Ollila D, Berry DA, Cirrincione C, et al. Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates: Surgical results from CALGB 40601 (Alliance). J Clin Oncol. 2013;31(suppl; abstr 501).