SABCS: Diverse Genetic Alterations Found in Residual Triple-Negative Breast Tumors After Neoadjuvant Chemotherapy

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(ChemotherapyAdvisor) – Triple-negative breast cancer cells that survive neoadjuvant chemotherapy harbor diverse genetic aberrations, some of which might provide promising targets for postsurgical therapies, according to study findings reported at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS).

The study “found some things that could be promising therapeutically, such as frequent MYC, MCL1 and JAK2 amplifications as well as mutations in the PI3K pathway,” said lead author Justin M. Balko, PharmD, PhD, of the Vanderbilt-Ingram Cancer Center in Nashville, TN.

Neoadjuvant chemotherapy is administered to shrink tumors, improving the likelihood of successful resection. It is an increasingly common component of treatment for triple-negative breast cancer, inducing a pathologic complete response (pCR) in approximately 30% of patients.

“Unfortunately, about 70% of patients still have some residual disease at the time of surgery, despite treatment,” Dr. Balko said. “We speculate this residual disease in the breast should look just like simultaneous micrometastases that are destined to recur in the same patient. Thus, we need to know what is in this tissue that is left behind to conceive targeted therapies to treat and prevent recurrence of metastases down the road.”

Residual cells are resistant to standard neoadjuvant chemotherapy, but if they harbor other “molecularly targetable” mutations, then targeted therapies after surgery might prevent or kill residual malignancies, possibly improving patients' prognoses, Dr. Balko noted.

Dr. Balko and his coauthors employed next-generation DNA sequencing to evaluate 182 oncogenes and tumor-suppressing genes in 81 evaluable triple-negative breast tumors from 102 patients, he reported.

Although most of the tumors (72/81; 89%) harbored TP53 mutations, diverse suites of genetic alterations were found overall, from tumor to tumor, Dr. Balko emphasized.

Altered PI3K/mTOR pathway genes were found in 33% of tumors, cell cycle gene alterations in 31%, and DNA repair pathway gene alterations in 20% of tumors, he reported. Ras/MAPK pathway (including KRAS, RAF1 and NF1 mutations) in 12% of tumors.

“The diversity of lesions in residual triple-negative breast cancers after neoadjuvant chemotherapy underscores the need for powerful and broad molecular approaches to identify actionable molecular alterations and, in turn, better inform personalized therapy of this aggressive disease,” Dr. Balko concluded. “Incorporation of this platform into clinical studies and eventually standards of care should aid in the prioritization of patients with residual disease after neoadjuvant chemotherapy into rational adjuvant studies.”

The study's findings need to be confirmed with a larger cohort of patients, he cautioned.

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