1. Goodwin, Peter M.

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CHICAGO-A gene test that predicts relapse in women with ER+ early breast cancer can identify patients with low-risk disease who could safely avoid extending their endocrine therapy beyond the standard 5 years, according to study findings reported in a poster session at the 2018 ASCO Annual Meeting (Abstract 516).

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Co-author Graham M. Poage, PhD, a scientist with Biotheranostics in La Jolla, Calif., said the Breast Cancer Index (BCI) test-a reverse transcription polymerase chain reaction (RT-PCR) 11-gene assay-is an endocrine therapy decision-making tool that identifies very low risk.


"These patients had a 20-year breast cancer-specific survival (BCCS) of 98 percent, which identifies a significant proportion of patients who potentially could be spared extended endocrine therapy because their risk is so low that continued therapy is unlikely to benefit [them]," said Poage. "There is no other assay like this."


New Analysis

The new study was a post hoc analysis of samples from the Stockholm clinical trial among patients with low-risk early breast cancer from 1976 to 1990 who had been randomized to treatment with or without adjuvant endocrine therapy.


The analysis was undertaken because recent trials of extending endocrine therapy beyond 5 years had suggested that only 3-5 percent of patients derived any benefit from longer treatment. But all patients were at risk of potentially debilitating side effects. So, it was important to establish criteria for sparing endocrine therapy among those who didn't need it.


"Patients [with] ER+ breast cancer have a profound, continued risk of recurrent breast cancer-distant metastases-going out to 20 years," Poage noted. And since patients were living longer and getting diagnosed earlier, many patients with ER+ disease developed recurrences. "So, we need an assay to help identify which of those patients-who are disease-free at year 5-will not have a breast cancer event out to 15-20 years," he said.


De-Escalating Therapy

The BCI 11-gene assay was able to identify patients likely to benefit from extending hormone therapy, Poage stated. "But this poster is about de-escalation of therapy-the contrary to that. [The study asks:] Which patients can we be pretty confident don't need continued endocrine therapy because their breast cancer-specific survival up to 20 years is profoundly high?"


The BCI assay had already been validated for breast cancer recurrence risk-stratification 10 years after initial therapy in ER+ early breast cancer. So, the new analysis was to identify patients who could remain free of recurrence beyond 10 years by using BCI to "interrogate" tumor biology with genomic markers that identify patients who had favorable prognoses.


Natural History

In the original Stockholm study, 1,780 patients with ER+ breast cancer were randomized to treatment with tamoxifen (for 2 or 5 years) or to no adjuvant therapy at all. "This [dataset] represents the natural history of breast cancer," Poage noted.


By using the BCI test on available tumor blocks from the Stockholm study, the new post hoc analysis was able to define a BCI score identifying patients who had at least 90 percent BCCS after 17 years of follow-up without having had any adjuvant systemic therapy. Statistical hazard models were then used to evaluate whether the BCI prognostic information was independent of traditional clinical and pathological factors.


Different Genes

Poage said the assay used different genes from other tests. "These 11 genes are not shared among the different assays. These are a distinct group of genes developed using an unbiased approach that was different from assays developed for the express use of chemotherapy decision-making."


The key issue was avoiding overtreatment, he noted. "Endocrine therapy is a not nearly as toxic as chemotherapy. So, the side effect profiles are less with hormonal therapies. But there are plenty of quality-of-life issues and there are some serious adverse events-especially as you treat for longer durations of time."


Avoiding Side Effects

The benefit from stopping endocrine therapy earlier rather than later was to stop unnecessary side effects in women who had "profoundly good" risk profiles, Poage explained. And he urged clinical teams to "allow biology to lead the way" (in therapy for patients with early-stage breast cancer)-which he called a "de-escalation" approach. "We are already doing that in the chemotherapy realm. The same can be applied to endocrine therapy," he said.


And while physicians were already using clinical factors to guide de-escalation, there was scope for refining endocrine-therapy de-escalation by using assays like the BCI. "This data shows that there are patients who are node-negative who may, or may not, have slightly elevated clinical risk profiles that can potentially be spared extended adjuvant hormonal therapy because they have such a low risk," he stated.


"As women live longer, we can pretty confidently identify subsets of them that are not going to recur." He regarded de-escalation as the new paradigm. "We can do that in the chemotherapy realm. We can also do it in the extended endocrine therapy realm using molecular assays as well as clinical factors. Both have a role to play in this era."


Peter M. Goodwin is a contributing writer.