Case: PIK3CA-Mutant Triple-Negative Breast Cancer Inhibited by Cetuximab

Breast Cancer

A woman with PIK3CA-mutant triple-negative breast cancer (TNBC), who is an exceptional responder to cetuximab, illustrates how PIK3CA mutations can induce tumor growth by activating the epidermal growth factor receptor (EGFR), and how these cancers may be successfully inhibited by EGFR inhibitors.

Joyce O’Shaughnessy, MD, Chair in Breast Cancer Research, Baylor-Sammons Cancer Center, Dallas, TX, presented the following case at PMO Live 2015.

A 34-year-old woman in her third trimester of pregnancy presented with a left breast mass, infraclavicular adenopathy, and lung metastases (grade 3 TNBC). Next-generation sequencing of the primary breast cancer shows p53 and PIK3CA mutations and wild-type BRCA1/2. She had no response to preoperative doxorubicin/cyclophosphamide. She delivered a healthy infant and on a clinical trial had a complete response in her breast, nodes, and lung to irinotecan/carboplatin plus cetuximab. The chemotherapy was stopped, and she continued on cetuximab alone.

Two years later, still on cetuximab, she developed a solitary recurrent lung metastasis, which was resected. The PIK3CA mutation in her solitary lung metastasis was lost. Chemotherapy with irinotecan/carboplatin (6 cycles) was reintroduced, and cetuximab was continued.

The patient is now more than 6 years out from the recurrence and still on cetuximab. A germline analysis revealed a germline mutation in the homologous recombination (HR) gene RAD51D.

A recent study reveals that PIK3CA-mutant TNBC is dependent on amphiregulin/EGFR/ERK signaling (Mol Cell Proteomics. 2015;14:1959-1976). Nine percent of TNBCs have PIK3CA mutations.

Her primary breast cancer showed 3+ phospho-AR and a very high level of phospho-ERK. The lung metastasis that lost PIK3CA shows no signaling through the MAP kinase pathway; signaling has switched through the PI3 kinase pathway, as EGFR expression has increased. In addition, phospho-AR has decreased to 1+.

“This case suggests that these PIK3CA-mutant TNBCs are dependent on amphiregulin and EGFR/ERK signaling. It may be, however, that these are exactly the ones that have overexpression of the androgen receptor,� said O’Shaughnessy. “We already know that androgen receptor expression in TNBC goes along with PIK3CA mutation, so these ligand-driven breast cancers respond better to antibodies than to tyrosine kinase inhibition.� These cancers may also benefit from enzalutamide because most are probably androgen receptor–positive as well.

This patient has a germline HR deficiency that is also somatically expressed. The question that arises, therefore, is whether an HR deficiency is required to achieve exceptional response with cetuximab in a PIK3CA-mutant TNBC, she said. A larger series will be needed to answer this question.

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