SABCS 2014 - Hormone Receptor Positive (HR+) BC

Predicting response to hormone therapy in neoadjuvant BC
JM Dixon et al. developed a binary assay that includes: a baseline assessment of mRNA expression of IL-6 related gene and the apoptotic neutral nerve growth factor receptor asociated protein; and also includes two proliferation markers on day 14 on Letrozole. This assay predicts with 96% accuracy the likelihood of response to hormone therapy. The investigators undertook sequential biopsies and subjected them to in-depth genomic analysis. They found that responding patients were losing mutations over time, and the contrary was true in non-responding patients. In Dr. Dixon's view, lack of early biologic effect has ominous implications to the natural history for the BC patient.

OPPORTUNE trial: Pictilisib + Anastrozole vs Anastrozole alone prior to surgery in HR+ BC
The addition of Pictilisib (formerly known as GDC-0941), a pan-PI3k inhibitor, to Anastrozole showed a marked decrease in the Ki67 proliferative index, restricted to the Luminal B cohort or patients. No apparent benefit was seen in the Luminal A patients. The FERGI trial was performed in with the same agent in the metastatic setting, and no clear benefit - so far.

Clinical benefit with 1st-Line hormonal therapy for metastastic breast cancer no different in visceral metastasis to non-visceral metastasis
Disease control of patients with visceral metastasis was carefully assessed in three large randomized trials in the 1st-line metastatic setting in hormone-sensitive breast cancer (Tamoxifen vs Exemestane; Tamoxifen vs Anastrozol; and Tamoxifen vs Fulvestrant). The investigators found that the clinical benefit in this visceral metastasis group was 58% (not unlike the 66% in the soft-tissue/bone metastasis group). Dr. John Robertson concludes that it is unlikely that any 1st-line chemotherapy will afford superior disease control. But he CONTRADICTS himself by stating that if the patient has life-threatening disease she should undergo chemotherapy. If hormone is as good as chemo, why not give it to the sickest?

FIRST trial: Fulvestrant 500 mg vs Anastrozole in 1st-line HR+ mBC
Again, Dr. Robertson, presents the results of this small (205 patient) phase-2 trial with the newer 500 mg formulation of Fulvestrant (a estrogen receptor (ER) inactivator) vs Anastrozole (as the control arm). Fulvestrant has three mechanisms of actions: 1. Blocks the dimerization of ER, 2. Begrades ER and 3. Impairs ER-related pathway cross-talk. The original primary endpoint was clinical benefit rate and it was previously reported. The investigators found a slightly superior, albeit non-statistically significant, clinical benefit rate in favor of the Fulvestrant arm (76% vs 67%). Overall survival was included in a protocol amendment in 2011, the results of which are presented for the first time at this meeting. And the results are impressive: 30% improvement in OS to 54 months median overall survival. We are waiting the results of the phase-3 FALCON trial in 2-3 years. Just a couple of decades ago, the median survival of this group of patients was 24 months.