Findings reported from the open-label, single-group, and mulitcenter phase II PAMELA trial, published last week in The Lancet Oncology*, have revealed that the HER2-E breast cancer subtype can predict which patients with early-stage HER2+ cancers are most likely to benefit from dual HER2 blockade therapies trastuzumab and lapatinib, without chemotherapy.
The study was designed to test the hypothesis that the HER2+/HER2-E intrinsic subtype benefits the most from dual HER2 blockade in the absence of chemotherapy and also serves as predictor of response following treatment -- as compared with patients with other HER2+ molecular subtypes; luminal A, luminal B, basal-like.
Led by Antonio Llombart-Cussac, Head of the Medical Oncology Service of the Hospital Arnau de Vilanova (Valencia, Spain), Javier Cortés, Associate Translational Investigator at the Vall d´Hebron Institute of Oncology (VHIO), and Head of the Breast Cancer Section and Gynecological Tumors at the Ramon y Cajal University Hospital (Madrid, Spain), and Aleix Prat, PI of VHIO´s Translational Genomics Group and Head of the Oncology Service at the Hospital Clínic de Barcelona -- all members of the cooperative academic breast cancer group SOLTI, the trial was performed in partnership with co-collaborators throughout several different sites across Spain and Italy.
Recruiting 151 patients with HER2-positive breast cancer, findings showed that up to 40% of patients with the HER2+ breast cancer subtype can avoid treatment with chemotherapy, as determined with the PAM50 preditctor test – results that were presented as first-outing data by Corresponding Author Aleix Prat, in an oral session during the 39th Annual San Antonio Breast Cancer Symposium (SABCS), 06 - 10 December 2016, Texas, USA.
Up until now, previous neoadjuvant studies in HER2+ breast cancer have shown that dual HER2 blockade without the combination of chemotherapy achieves pathological complete response (pCR – absence of residual tumor as well as metastasis) rates of between 6 - 36%. HER2+ breast cancer is not biologically homogeneous and not all subtypes of HER2+ tumors respond the same to this therapy. Among the existing genomic subtypes of HER2+ diseases established through PAM50, HER2-E presents the greatest activation of the EGFR/HER2 signaling pathway.
Centered on evaluating the potential predictive value of intrinsic PAM50 subtypes in gauging pCR in breast tissue following 18 weeks´ treatment with dual neoadjuvant therapy -- prior to surgery, complete pathological response in HER2-E breast tumors versus non-HER-2 subtypes in 151 patients was compared, and pCR was subsequently and significantly higher in HER2-E – 40.6% and 10% respectively.
The PAM50 HER2-E genomic subtype can therefore better guide the identification of patients with HER2+ disease who would most likely derive greater benefit from dual anti-HER2 therapies. Furthermore, early changes in gene expression indicative of a reduction of tumor cellularity are predictive of pCR at surgery.
Considering the major challenge of identifying novel biomarkers that can more precisely indicate which patients are more sensitive to therapy, these latest results represent an important forward-step in more effectively matching treatments to the disease specificities of individual patients based on genomic profiling.
“PAM50 testing prior to treatment and in the second week of therapy facilitates much more predictive data beyond hormone receptors. The PAMELA study opens important avenues for future research aimed at evaluating long term survival of patients with HER2-positive disease receiving dual HER2 blockade without chemotherapy,” conclude Cortés and Prat, co-authors of this recent Article.
* Antonio Llombart-Cussac, MD, Javier Cortés, MD, Laia Paré, PhD, Patricia Galván, BS, Begoña Bermejo, MD, Noelia Martínez, MD, Maria Vidal, MD, Sònia Pernas, MD, Rafael López, MD, Montserrat Muñoz, MD, Paolo Nuciforo, MD, Serafín Morales, MD, Mafalda Oliveira, MD, Lorena de la Peña, PhD, Alexandra Peláez, MD, Dr Aleix Prat, MD. 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. Published Online First 23 February 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30021-9.