PIK3CA Activating Mutations: A Discordant Role in Early Versus Advanced Hormone-Dependent Estrogen Receptor–Positive Breast Cancer?

The phosphoinositide-3 kinase (PI3K)/AKT signaling network is the most frequently mutated pathway in breast cancer. Somatic alterations in the PI3K/AKT pathway include mutation and/or amplification of the genes encoding the PI3K catalytic subunits p110 (PIK3CA) and p110 (PIK3CB), the PI3K regulatory subunit p85 (PIK3R1), the PI3K effectors AKT1, AKT2, and PDK1, and loss of the lipid phosphatases PTEN and INPP4B. PIK3CA mutations are the most common genetic alteration of this pathway; 80% or more occur within the helical (E542K, E545K) and kinase (H1047R) domains of p110 . Such mutations confer increased catalytic activity for the generation of the second messenger phosphatidylinositol (3,4,5)triphosphate (PIP3). PIP3 recruits PH domain–containing kinases, such as AKT, PDK1, SGK, and so on to the plasma membrane, where they become activated to induce enhanced cell proliferation and survival. PIK3CA mutations induce a transformed phenotype in vitro and in vivo, including growth factor independence, anchorageindependent growth, metastatic mammary tumors in transgenic mice, resistance to anoikis, and drug resistance. Approximately 40% of estrogen receptor (ER) –positive breast cancers harbor activating mutations in PIK3CA. Some studies have suggested that ER-positive/PIK3CA mutant tumors or ERpositive cancers with aberrant PI3K signaling exhibit a lower response to antiestrogens compared with ER-positive/PIK3CA wild-type tumors, but the literature is mixed with respect to this association. In the article that accompanies this editorial, Sabine et al report a focused analysis of mutations in the PI3K/AKT and RAS/RAF pathways using DNA extracted from formalin-fixed, paraffin-embedded tumor sections of 4,294 postmenopausal patients with ER-positive breast cancer who participated in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial. This study randomly assigned patients to exemestane versus tamoxifen followed by exemestane for a total of 5 years of adjuvant treatment. PIK3CA mutations were found in approximately 40% of the analyzed cancers; as expected, the majority of mutations were on the helical and kinase domain hotspots. RAS mutations, however, were rare. The authors did not see a difference in outcome associated with PIK3CA mutations, regardless of location of mutation (helical or kinase) or type of endocrine therapy used. Consistent with previous reports, the presence of PIK3CA mutations was associated with so-called good prognosis tumors: lower grade, less lymph node involvement, and progesterone receptor positivity. The authors appropriately concluded that the presence of PIK3CA mutations does not affect the risk of recurrence of early ER-positive breast cancer treated with adjuvant endocrine therapy. In patients with acquired resistance to endocrine therapy, the value of the combined inhibition of ER and the PI3K/AKT/target of rapamycin (TOR) pathway is supported by recent clinical trials. The phase II Tamoxifen Plus Everolimus (TAMRAD) study, conducted in postmenopausal patients with ER-positive metastatic breast cancer who had progressed during treatment with an aromatase inhibitor, found that the addition of everolimus (a small molecule inhibitor of TORC1, downstream of PI3K/AKT) to tamoxifen resulted in a 46% reduction in the risk of progression compared with tamoxifen alone. A subgroup analysis revealed that in the tamoxifen-everolimus arm, this risk reduction was greatest (54%) among patients with secondary resistance to endocrine treatment. A significantly higher clinical benefit rate (defined as the absence of progression at 6 months) was also observed in patients with secondary endocrine resistance who received the combination compared with single-agent tamoxifen. The benefit of everolimus in antiestrogen-resistant advanced breast cancer was further shown by the phase III Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study, which randomly assigned patients with ER-positive metastatic breast cancer who had progressed during treatment with first-line endocrine therapy with an aromatase inhibitor to exemestane versus exemestane plus everolimus. Patients treated with the combination exhibited a significant increase in progression-free survival compared with patients treated with exemestane alone. This result led to the approval by the US Food and Drug Administration of the combination of everolimus plus exemestane for patients with ER-positive advanced breast cancer refractory to previous endocrine therapy. Notably, next-generation DNA sequencing of a fraction of the tumors of patients enrolled onto BOLERO-2 suggested that cancers benefited from the combination regardless of the presence of a PIK3CA mutation. This clinical activity is also consistent with reports showing that hyperactivation of the PI3K/AKT pathway confers adaptation to estrogen deprivation in experimental models of hormone-dependent breast cancer. In these studies, PI3K/AKT/TOR inhibitors abrogated JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 27 SEPTEMBER 2