In The Literature – October 2014

October 2014, Vol 5 , No 8 - In the Literature

PIK3CA Mutations Associated with Favorable Prognostic Factors in Breast Cancer
Deregulation of the phosphoinosit­ide 3-kinase (PI3K)/AKT–signaling network may contribute to endocrine resistance in patients with breast cancer. PIK3CA is the most frequently mutated gene in luminal breast cancer. Studies have shown that therapeutic agents targeting the PI3K/AKT pathway are effective for the treatment of luminal cancers, whereas coordinate PIK3CA/RAS mutations may be linked with relapse during endocrine therapy and may predict response to mTOR inhibitors.

However, controversy remains over the clinical effect of PIK3CA mutations in the helical versus kinase domains. In a new study, researchers analyzed mutations in the PI3K/AKT and RAS/RAF pathways to determine if improved outcomes occur in patients with estrogen receptor (ER)-positive breast cancer and PIK3CA mutations who are receiving endocrine therapy (Sabine VS, et al. J Clin Oncol. 2014;32:2951-2958).

The study included 4540 postmenopausal women with ER-positive breast cancer who were receiving endocrine therapy and participating in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial. TEAM is a multinational, randomized, open-label, phase 3 clinical trial of 9776 postmenopausal women with hormone receptor–positive luminal early breast cancer comparing exemestane (Aromasin) 25 mg once daily or tamoxifen (Nolvadex) 20 mg once daily, followed by exemestane for a total of 5 years of adjuvant treatment.

For this study, researchers used DNA extracted from formalin-fixed paraffin-embedded breast cancer samples of 4294 patients who had complete mutational data available. Mutational analyses were performed for 26 mutations across 6 genes.

PIK3CA mutations were found in 39.8% of the samples; the majority (89.8%) of mutations were on the helical or kinase domains, of which 79.7% were in 3 known hotspots. RAS/RAF mutations, however, were rare (0.6%). The researchers did not see significant differences in patient outcomes associated with PIK3CA mutations (helical or kinase) or the endocrine therapy used.

In univariable analyses, PIK3CA mutations were associated with a 24% reduction in the risk of distant metastasis at 5 years. Despite this risk reduction, a multivariable analysis correcting for known clinical and biological prognostic factors failed to demonstrate that PIK3CA mutation is an independent prognostic marker for distant relapse-free survival (hazard ratio, 0.92; 95% confidence interval, 0.75-1.12).

The researchers found that the presence of PIK3CA mutations was associated with favorable prognostic factors, including progesterone receptor positivity, low tumor grade, and less lymph node involvement.

Although approximately 40% PIK3CA mutations were exhibited within luminal breast cancer samples, PIK3CA mutations were not shown to act as an independent predictor of risk of the recurrence of early ER-positive breast cancer treated with adjuvant endocrine therapy, concluded the researchers.

Coexistence of BRAF and TERT Mutations Identified in Papillary Thyroid Cancer
Among all thyroid cancers, papillary thyroid cancer (PTC) accounts for 80% to 85% of thyroid malignancies. Studies have shown that the BRAF V600E mutation is found in PTC and conventional PTC. Recently, researchers identified telomerase reverse transcriptase (TERT) promoter mutation chr5:1,295,288C>T (C228T) in thyroid cancers. In a new study, researchers investigated the prognostic value of the BRAF V600E and TERT C228T mutations, individually and cooperatively, in a large cohort of patients with PTC (Xing M, et al. J Clin Oncol. 2014;32:2718-2726).

The retrospective study examined the relationship of BRAF and TERT C228T in 507 patients aged 45.9 ± 14 years who were treated for PTC over a 12-year period (1990-2012) at Johns Hopkins Hospital. The median follow-up was 24 months (interquartile range, 8-78 months) after the initial treatments.

Researchers found the coexistence of the BRAF V600E and TERT C228T mutations in 6.9% of all subtypes of PTC and 7.3% of conventional PTC. Both mutations were more frequently associated with high-risk clinicopathologic characteristics of PTC than they were individually.

Tumor recurrence rates per 1000 person-years were 25.8% versus 9.6%, respectively, in BRAF mutation-positive patients compared with BRAF mutation-negative patients (hazard ratio [HR], 3.22; 95% confidence interval [CI], 2.05-5.07) and 47.5% and 11.4% in TERT C228T mutation-positive patients and TERT C228T mutation-negative patients (HR, 3.46; 95% CI, 2.19-5.45). The recurrence rate per 1000 person-years for patients with PTC harboring both mutations was also significantly higher compared with patients with neither mutation (68.6% vs 8.7%, respectively; HR, 8.51; 95% CI, 4.84-14.97), suggesting a synergistic effect of the coexisting 2 mutations.

These results were found in the overall analyses of both PTCs and of the conventional PTC variant. Furthermore, an analysis of disease-free survival rates demonstrated a moderate decline with BRAF V600E or TERT C228T independently, but a sharp decline with 2 coexisting mutations. Similar results were found in the analyses of conventional PTCs.

The coexistence of BRAF V600E and TERT C228T identifies a unique genetic background for the most aggressive subgroup of patients with PTC, whereas the 2 mutations individually have less impact on the aggressiveness of PTC. These genetic patterns have important prognostic and therapeutic implications in the management of PTC.

Novel Mutations Identified Can Help to Overcome Treatment Resistance in Lung Cancer
Crizotinib (Xalkori), a first-generation ALK tyrosine kinase inhibitor (TKI), is a standard therapy for patients with ALK-rearranged non–small-cell lung cancer (NSCLC). However, most patients will develop resistance to crizotinib within 1 to 2 years, and this has led to the development of next-generation ALK-TKI agents, including alectinib (not yet approved by the FDA) and the recently approved ceritinib (Zykadia). Because patients still relapse during therapy with these next-generation ALK-TKIs, which limits their clinical benefits, a new study examined the mechanisms of resistance to alectinib and looked for potential strategies to overcome this resistance. Alectinib was chosen for this as one of the most advanced next-generation ALK inhibitors (Katayama R, et al. Clin Cancer Res. 2014 Sep 16. Epub ahead of print).

To determine why ALK-positive lung cancers become resistant to alectinib, the researchers examined 2 different methods. They established a cell-line model of acquired resistance to alectinib in the laboratory and analyzed a primary tumor sample from a patient with alectinib-refractory disease. They engineered Ba/F3 models harboring alectinib-resistant ALK mutations and assessed the potency of other next-generation ALK-TKIs in these models. They then tested the antitumor activity of ceritinib in patients with advanced ALK-positive NSCLC whose disease had relapsed while receiving alectinib.

The researchers identified 2 novel secondary ALK mutations—a V1180L gatekeeper mutation from the cell-line model and an I1171T mutation from the patient who developed resistance to alectinib, both of which were still sensitive to ceritinib in vitro. The 2 mutations confer resistance to crizotinib as well as to alectinib, and thus add to the growing list of secondary ALK mutations that can mediate re­sistance to crizotinib.

Furthermore, treatment of the patients with ceritinib led to significant tumor regression, which lasted for 7 months. Thermodynamic simulation suggests that V1180L and I1171T mutations cause resistance by decreasing the binding affinity with alectinib.

The ability of ceritinib to overcome ALK mutations in patients who develop resistance to alectinib suggests a potential role for multiple, sequential therapy with various ALK inhibitors, depending on the underlying resistance mechanism.

Overall, these findings underscore the importance of serial biopsies to follow the evolution of drug resistance and to identify the best therapeutic strategies that will most likely provide clinical benefit for patients based on the underlying molecular alterations.