Results presented at the San Antonio Breast Cancer Symposium (SABCS), being held December 10?14, 2013 in San Antonio, Texas, show that women with breast cancer characterized by high levels of the protein HER2 and hormone receptors gained much less benefit from presurgery treatment with chemotherapy and HER2-targeted therapies if their cancer had one or more mutations in a protein-coding gene called PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha).[1][2]
In some women with breast cancer treated with neo-adjuvant therapy or treatment before surgery, no residual invasive cancer can be detected in breast tissue samples and lymph nodes removed during surgery. Emerging data suggest that these women, who are said to have had a pathologic complete response, have a greater chance of long-term survival compared with women who do not have a pathologic complete response.
Common genetic aberrations
?Mutations in the PIK3CA gene are among the most common genetic aberrations in breast cancer,? noted Sibylle Loibl, M.D., professor at the German Breast Group in Neu-Isenburg, Germany. ?We found that very few women with HER2- and hormone receptor-positive breast cancer with a PIK3CA mutation experienced a pathologic complete response after receiving neoadjuvant therapy. We need to identify new treatment options for this group of patients and evaluate them in clinical trials,? Loibl continued.
We? need to integrate PIK3CA mutation analysis of breast tumors into routine practice so that we can ensure women receive the most appropriate neoadjuvant therapy for their tumor type…
Integrated in routine practice
?We also need to integrate PIK3CA mutation analysis of breast tumors into routine practice so that we can ensure women receive the most appropriate neoadjuvant therapy for their tumor type.?
GeparSixto trial
Loibl and colleagues investigated whether the presence of a PIK3CA mutation affected patients enrolled in the GeparSixto or G6 clinical trial in experiencing a pathologic complete response after neoadjuvant therapy. There were 595 participants in the G6 clinical trial, and information on the presence or absence of PIK3CA gene mutations was available for 512,240 with HER2-postive breast cancer and 272 with triple-negative breast cancer.[3]
Participants in the GeparSixto trial received neoadjuvant chemotherapy with paclitaxel (Taxol?; Bristol-Myers Squibb Company) and nonpegylated-liposomal doxorubicin (Myocet?; Teva) and were randomly assigned the chemotherapy carboplatin (Paraplatin?; Bristol-Myers Squibb Company and generic) or no additional chemotherapy. Patients with HER2-positive disease also received neo-adjuvant trastuzumab and lapatinib, two HER2-targeted therapies, while patients with triple-negative disease also received neoadjuvant bevacizumab.
Loibl and colleagues found that patients with HER2-postive breast cancer were more likely to have at least one PIK3CA mutation in their tumor compared with women with triple-negative breast cancer. Overall, the pathologic complete response rate was lower among women with at least one PIK3CA mutation in their tumor compared with women without a PIK3CA mutation, but the effect was only significant among the group of women with HER2- and hormone receptor-positive breast cancer. Among these women, patients with a PIK3CA mutation had a pathologic complete response rate of only 6.5% compared with 30.8% for those without a PIK3CA mutation.
GeparQuinto trial
?To evaluate these findings in a group with only one HER2 treatment, we are currently analyzing data from another clinical trial, called the GeparQuinto trial. This trial is a randomized, phase III clinical trial evaluating two different neoadjuvant therapy regimens with a single anti-HER2 treatment, trastuzumab (Herceptin?; Roche/Genentech) or lapatinib (Tykerb?; GlaxoSmithKline) for women with HER2-positive breast cancer,? Loibl said. [4]
This study was supported by funds from the European Commission?s Seventh RTD Framework Programme grant number 278659 ?RESPONSIFY.?
For more information:
[1] Loibl S, Denkert C, Schneeweis A, Paepke S, Lehmann A, Rezai M, Zahm DM, Sinn P, et al. PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer ? Prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. Publication Number: S4-06
Presented by: Sibylle Loibl, M.D.
[2] Buttitta F, Felicioni L, Barassi F, Martella C, Paolizzi D, Fresu G, Salvatore S,et al. PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol. 2006 Feb;208(3):350-5.[Article][PubMed]
[3] NCT01426880 – Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer (GeparSixto) [Study Record Detail]
[4] NCT00567554 – A Phase III Trials Program Exploring the Integration of Bevacizumab, Everolimus (RAD001), and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer (GeparQuinto) [Study Record Detail]
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