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The researchers found that the mice treated with letrozole gained more weight and had increased insulin resistance compared with mice given placebo, but that cohousing mitigated these developments. Testosterone and luteinizing hormone levels rose for letrozole-treated mice housed together, whereas the cohoused mice had normal testosterone and LH levels and experienced normal estrous cycling and ovulation.

Thackray and colleagues also observed a shift toward similar gut microbiomes in the cohoused mice, which she said indicated that “there is an exchange of microbes between these two groups.” Additional analysis revealed that the bacteria Coprobacillus changed when comparing letrozole-treated mice housed together and letrozole-treated mice in the cohousing group, indicating that this specific bacteria “potentially could be a probiotic that we can test as a potential treatment for protecting or preventing the development of PCOS,” Thackray said during a press conference.

“This cohousing approach suggests that the changes that we see in the microbiome are not just a result of PCOS, but it may actually play a causal role,” Thackray said. “Fundamentally, this is suggesting that modulation of the gut microbiome could be a potential therapy for PCOS. We’d like to follow this up with our mouse model, with the eventual goal of developing new therapeutics for women with PCOS.” – by Phil Neuffer

Women with metastatic hormone-sensitive breast cancer lived nearly 8 months longer with the addition of fulvestrant (Faslodex) to first-line anastrozole (Arimidex), long-term results of a phase III trial showed.

In the study of nearly 700 patients, overall survival (OS) in the combination arm was 49.8 months versus 42.0 months with anastrozole alone at 7 years median follow-up (HR 0.82, 95% CI 0.69-0.98, P=0.03), Rita S. Mehta, MD, of the University of California, Irvine, and colleagues reported.

At 5 years, 42% of patients in the combination arm were still alive compared with 33% in the anastrozole arm, despite nearly half the women in the control arm crossing over to fulvestrant, a selective estrogen-receptor down-regulator, after disease progression, they wrote in the New England Journal of Medicine.

Mehta told MedPage Today that until now, first-line metastatic breast cancer trials have shown improvements in progression-free survival (PFS) but not OS.

“If we don’t see a survival benefit with newer agents compared to old agents, then we haven’t really moved the needle,” she said. “Ultimately patients want to see if they can live longer or not.”

Early findings from SWOG S0226 were first reported by Mehta in 2011, at a median 3 years follow-up, and showed a significant PFS benefit with the combination (15.0 vs 13.5 months) and a trend toward improved OS.

“Some physicians changed their practice back then — some were not convinced,” Mehta said. “But now they should be convinced, because now we have one of the longest follow-ups and one of the largest studies.”

The current study, SWOG Cancer Research Network S0226, examined outcomes of 694 women randomized 1:1 to standard-dose anastrozole or the combination of anastrozole plus intramuscular fulvestrant. Patients were stratified by prior use of tamoxifen. All patients had hormone receptor-positive disease.

Further subgroup analyses for OS in the updated findings showed no benefit for the combination among those whose disease progressed from 5 to 10 years from their initial breast cancer diagnosis (HR 1.01, 95% CI 0.69-1.48) and in patients not sensitive to endocrine therapy (HR 1.08, 95% CI 0.64-1.80).

Mehta noted that with the longer follow-up, there were no additional grade 4/5 adverse events (AEs) on the combination arm. “In fact, if there was any additional grade 4 toxicity it was on the anastrozole arm,” she said.

Previous grade 4 AEs in the combination arm included arthralgia, dyspnea, thrombosis or embolism, and thrombocytopenia, each occurring in one patient, and there were three treatment-related deaths in the combination arm — all previously reported.

Grade 3 toxicities were similar between the two arms, at 15% of patients on the combination and 13% of those on anastrozole-alone (P=0.47). The most common grade 3 AEs (ranging from 1% to 4%) were fatigue, GI symptoms, hot flashes, mood alterations, and musculoskeletal pain. Treatment discontinuation due to AEs were rare — 12 patients on the combination and five on anastrozole alone.

The results in a nonhuman primate corroborate many of the symptoms reported by women taking AIs and reveal detrimental effects of these treatments on the brain, in part through elevated hippocampal E2 levels,” the researchers concluded. “Future studies are needed to elucidate the precise mechanisms by which AIs compromise the CNS.”