Dual HER2 Blockade without Chemotherapy a Possibility for HER2-Enriched Breast Cancer

TON Web Exclusives - Breast Cancer

The HER2-enriched subtype is a strong predictor of sensitivity to dual HER2 blockade within HER2-positive breast cancer in the absence of chemotherapy, according to results of the nonrandomized PAMELA trial that were recently presented at the 2016 San Antonio Breast Cancer Symposium. The study corroborates the clinical and biologic heterogeneity of HER2-positive breast cancer using gene expression analysis.

In the trial, the HER2-enriched subtype predicted pathologic complete response (pCR) following neoadjuvant lapatinib and trastuzumab, reported Aleix Prat, MD, PhD, from the August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.

PAMELA was an open-label, multicenter, prospective translational research study conducted in 151 women with stage I-IIIA HER2-positive breast cancer.

According to Dr Prat, PAMELA provides independent confirmation that characterization of PAM50 breast cancer subtype can identify molecular profiles of patients who may safely be spared chemotherapy compared with hormone receptor (HR) status. Until recently, HR status was the only molecular marker that consistently predicted pCR in HER2-positive disease in the absence of chemotherapy.

Prat and colleagues sought to identify profiles predictive of clinical benefit from targeted therapy, using the PAM50 intrinsic subtype predictor, compared with traditional clinical HER2 classification. Patients were treated with dual HER2 blockade consisting of lapatinib 1000 mg/day and trastuzumab 6 mg/kg every 3 weeks, for 18 weeks. If the tumor was HR-positive, patients could also receive endocrine therapy during the same 18 weeks.

Intrinsic subtyping was performed at baseline and at week 2, and a mandatory ultrasound was performed at week 6. With an increase in tumor size, paclitaxel 80 mg/m2 weekly, for 12 weeks, was added to dual HER2 blockade. If the patient was receiving endocrine therapy prior to progression, it was withdrawn before chemotherapy was administered.

Of the 151 patients enrolled, 77 were HR-positive, of whom 88.3% completed treatment, and 74 were HR-negative, of whom 93.2% completed treatment. Approximately 60% of women were postmenopausal at baseline. The primary outcome measure was pCR at the time of surgery, predicted by PAM50 HER2-enriched subtype.

Two-thirds (66.9%) of tumor tissue samples at baseline were HER2-enriched, “demonstrating that HER2-positive disease is heterogeneous,” said Dr Prat. Luminal tumors were identified in 49% of HR-positive disease, and basal-like subtype was identified in 12.2% of HR-negative samples. The rates of HER2-enriched tumors that were of the HER2-enriched subtype by gene expression were 49.3% in HR-positive samples and 85.1% in HR-negative samples.

The rate of pCR in the breast was 40.6% in women with HER2-enriched tumors at baseline compared with 10.0% in those with non–HER2-enriched tumors. In the breast/axilla, pCR rates were 34.7% in HER2-enriched tumors and 10.0% in non–HER2-enriched tumors. “We showed that around 50% of tumors at week 2 become normal by gene expression, and if that happens, the probability of having a pCR is around 50%, much higher than if you don’t become normal,” Dr Prat reported.

“We believe that the studies evaluating the long-term survival outcomes of chemotherapy-free dual HER2 blockade seem justified after selecting patients based on variables such as intrinsic subtyping, HR status, response at week 2, and pathological response at surgery,” he concluded.

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Last modified: April 7, 2017