CALGB (former name: Acute Leukemia Group B, ALGB) is a cancer research cooperative group in the U.S. CALGB research is focused on seven major disease areas: leukemia, lymphoma, breast cancer, lung cancer, gastrointestinal malignancies, genito-urinary malignancies, and melanoma.
Recent trials in HER2-positive (HER2+) breast cancer demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting. This study aimed to further quantify the pathological complete response (pCR) rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents.
This trial seeks to evaluate mutational landscape of 181 HER2+ pretreatment tumors and to correlate mutations in nine genes with pCR to chemotherapy plus HER2 targeting. The focus is on three genes, primarily TP53, PIK3CA, HER2.
Primary endpoint: pCR
Pathological Complete Response (pCR to) in dual therapy (THL) vs. single therapy (TH) was 56% vs. 46% but this difference was not statistically significant, meaning that certain HER2+ early-stage breast cancer patients may not benefit from more aggressive chemotherapy treatments as part of a neoadjuvant regimen.
As no difference in pCR was observed with treatment of HER2+ tumors with THL vs TH, the tumors were further divided into intrinsic subtypes to see if this additional categorization could explain the results. The subtypes were HER2 enriched, Luminal A and Luminal B. These subtypes were associated with a number of mutations – the most common being TP53 (56%) and PIK3CA (20%).
TP53 was the most frequently mutated gene (56% overall), and this mutation was associated with an increased pCR. Additionally, mutations in PIK3CA (and other mutations seen less commonly) were not associated with pCR.
Further studies are being conducted to simultaneously use genomic signatures, somatic mutations and clinical variables to more accurately predict pathological complete responses. The results of these studies should be able to guide more targeted and effective therapies.
As we begin to understand more about tumor types (and subtypes, genetic mutations and other differences) we realize that determining effective treatment of breast cancer requires more than relying on markers such as HER2 positivity. While markers such as HER2 are helpful, it is becoming increasingly clear that there are many other factors involved. Additional studies are underway to help us understand the various factors that impact therapy and guide increasing specific and effective therapies.
Mutational analysis of CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer, presented by Katherine Hoadley, PhD, Research Assistant Professor in the Department of Genetics at UNC Lineberger.