HER2-Enriched Subtype Predicts Response to Dual HER2 Blockade in Early Breast Cancer

Aleix Prat, MD, PhD

Women with the HER2-enriched subtype of early-stage, HER2-positive breast cancer were more likely to have a pathological complete response (pCR) when treated with dual HER2-blockade, according to results from the PAMELA trial published in The Lancet Oncology.

Among 151 women in the nonrandomized, open-label PAMELA study who had a pCR when treated with lapatinib (Tykerb) and trastuzumab (Herceptin), 41% (41/101) had the HER2-enriched subtype as compared with just 10% (5/50) who who had one of the other subtypes (odds ratio [OR] = 6.2; 95% CI, 2.3-16.8; P = .0004). The PAMELA findings were initially reported at the 2016 San Antonio Breast Cancer Symposium.

“This is one of the first studies to prospectively test the ability of a genomic biomarker to predict response to anti-HER2 therapy,” lead researcher Aleix Prat, MD, PhD, said in an interview with OncLive. “Our results show that patients exquisitely sensitive to anti-HER2 therapies without chemotherapy can be identified.”

Prat, who is head of medical oncology at August Pi i Sunyer Biomedical Research Institute in Barcelona, Spain, added that the presence of the HER2-enriched subtype was not yet strong enough to guide treatment decisions, but could be effective when used in concert with other markers.

“Combining information such as subtype (HER2-enriched vs not), response at week 2 and response at surgery (pCR versus not), might help us identify these patients that are exquisitely sensitive to anti-HER2 therapies and do not need chemotherapy,” said Prat.

He went on to say that researchers are also trying to understand why most women with the HER2-enriched subtype (59%) did not respond strongly to the HER2 blockade. “We know there is still biological heterogeneity even within a subtype. For example, a subset of HER2-enriched tumors has PIK3CA mutations, a potential biomarker of response. Thus, we are currently working on analyzing this biological heterogeneity within HER2-enriched to identify additional biomarkers of response beyond subtype.”

From October 2013 to November 2015, researchers for the PAMELA trial recruited 151 women at 19 hospitals in Spain. All patients were diagnosed with previously untreated, centrally confirmed HER2-positive, stage I to IIIA invasive breast cancer.

Patients were assigned to a loading dose of 8 mg/kg of IV trastuzumab followed by 6 mg/kg of IV trastuzumab every 3 weeks, along with 1000 mg daily oral lapatinib for 18 weeks, followed by surgery 1 to 3 weeks after last dose. Patients with HR-positive disease were also treated with letrozole or tamoxifen, depending on menopausal status and all patients were recommended to receive postoperative chemotherapy.

Using PAM50 gene expression profiling, researchers performed intrinsic subtyping at baseline and at week 2, and patients underwent a mandatory ultrasound at week 6. Patients who experienced any increase in tumor size were assigned to paclitaxel at 80 mg/m² weekly for 12 weeks. Trastuzumab was maintained at the original dosage and lapatinib was reduced to 750 mg daily. Endocrine therapy was stopped before initiating chemotherapy in patients with progressive disease.

Tumors were classified as 1 of 5 intrinsic molecular subtypes—luminal A, luminal B, HER2-enriched, basal-like, and normal-like. About two-thirds of patients had the HER2-enriched subtype at baseline and a total of 101 women were positive for the subtype. Fifty women in the study were positive for 1 of the 4 other subtypes.

In multivariate analysis, OR was 4.0 (95% CI, 1.3-12.5; P = .016) for pCR among patients with the HER2-enriched subtype compared with patients with non-HER2—enriched subtypes.

Researchers expected more women with the subtype to have pCR, but the absolute difference between the 2 groups (31%) was higher than the preplanned threshold (27%). Of 22 patients with luminal A subtype at baseline, none had a pCR. Only 11% of patients with basal-like disease at baseline achieved a pCR, though they also had HR-negative disease.

Prat said that researchers in Barcelona are currently working with the Translational Breast Cancer Research Consortium group in the United States to design a prospective trial demonstrating that a subset of patients with HER2-positive disease can be cured following anti-HER2 therapies without the need of chemotherapy. In an accompanying editorial, Aju Mathew, MD, and Adam Brufsky, MD, PhD, wrote that the existing data is not yet strong enough to recommend eliminating chemotherapy for all patients with HER2-positive breast cancer, but deintensification of therapy is a goal worth pursuing.²

“Results of the PAMELA trial provide valuable insights into how such a regimen can be used in patients who prefer a non-chemotherapeutic option or in those who are poor candidates for chemotherapy,” they wrote. “Results of the PAMELA trial shed light into the type of tumors that would need only HER2 blockade to achieve pathological complete response…Pathological complete response is an effective surrogate marker for improved survival outcomes, and further trials assessing intrinsic molecular subtypes are justified. These trials should contribute substantially to the study of treatment de-intensification in patients with early-stage HER2-positive breast cancer.”

References

1. Llombart-Cussac A, Cortés J, Paré L, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017;18:545-554.
2. Mathew A, Brufsky A. Less is more? De-intensification of therapy for early-stage HER2-positive breast cancer. Lancet Oncol. 2017;18:428-429.