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ASCO Data Pushes Boundaries for Genomic Testing in Localized Breast Cancer

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NEW YORK (Precision Oncology News) – Two studies presented at the American Society of Clinical Oncology annual meeting last week addressed open questions on the use of breast cancer molecular recurrence risk tests for women with early-stage hormone receptor-positive tumors. While one study explored the combination of Genomic Health's Oncotype DX test with clinical risk information, the other reported on the ability of Biotheranostics' Breast Cancer Index test to predict benefit from extended endocrine therapy.

The results address some of the unknowns that clinicians have said remain following the publication last year of long-term data from Genomic Health's TAILORx trial, including how molecular risk information should be used in the care of younger breast cancer patients, and whether it can stratify women into groups receiving longer or shorter hormonal treatment regimens.

In a new analysis of TAILORx data last week, Joseph Sparano, the trial's lead investigator, shared data on the additive value of clinical risk information to molecular testing, both overall and in resolving uncertainty about observed benefits to younger women from added chemotherapy in the trial despite low-risk Oncotype recurrence scores. Full data were simultaneously published in the New England Journal of Medicine last week.

The focus on clinical factors is notable, considering that Genomic Health has in the past sought to distinguish its test from competitors by stressing that it offers a purely genomic risk assessment, independent of clinical features, for its predictive power.

According to Sparano, the results of TAILORx last year showed definitively that Genomic Health's test is predictive of a "large chemotherapy benefit" if a woman's recurrence score is greater than 25, and a lack thereof if it is 25 or lower, and the new analysis doesn’t change that.

Trial investigators had seen last year, however, a "three-way interaction between age, recurrence score, and chemotherapy use," resulting in evidence of an absolute chemo benefit in women 50 or younger with mid-range recurrence scores, which merited further exploration.

The new analysis sought to investigate whether pathologic features, which don't necessarily correlate with Oncotype recurrence scores, could add to prognostic assessment of breast cancer patients overall, and specifically those under 50, helping oncologists decide how to treat them.

According to Sparano, while clinical factors showed prognostic power throughout the cohort, they failed to predict chemotherapy benefit in the full study population on their own.

Further analyses painted an even more differentiated picture, according to his ASCO presentation. In the primary TAILORx analysis, irrespective of clinical risk, women 50 or younger with mid-range recurrence scores — from 16 to 25 — had an absolute chemo benefit of 1.6 percent for scores up to 20 and 6.5 percent for scores from 21 to 25, for example.

In contrast, when clinical risk was compared for these patients, it defined different levels of absolute chemo benefit. For the recurrence score 21-to-25 group, chemo benefit was evident for both clinically high- and low-risk women, ranging from 6 percent to 9 percent. However, in the 16-to-20 score group, only those with high clinical risk showed a notable absolute benefit from chemo — about 6.5 percent compared to just 0.2 percent in clinically low-risk women.

The implication of the calculation is that because there was so little absolute benefit from added chemo in the subset of younger women in the trial who had both a low risk score (16 to 20) and low clinical risk, this combination of biomarkers could help clinicians avoid unnecessary treatment for this group.

Genomic Health highlighted the analysis as providing a rationale for a shift in how Oncotype DX may be used in the clinic for younger women.

"With this new analysis, it is clear that women age 50 or younger with a recurrence score result between 16 and 20 and low clinical risk do not need chemotherapy," Sparano said.

Evidence for ovarian suppression

An even more nuanced picture about the population most likely to benefit from chemo emerged from Sparano and colleagues' exploratory analysis of age at diagnosis. "We see benefit for women 46 to 50 who are premenopausal, but not postmenopausal, and a trend towards chemo benefit in women age 41 to 45, but no benefit in women 40 or under who are less likely to develop premature menopause as a consequence of cytotoxic chemotherapy," he explained at ASCO.

Taken together, Sparano said the findings indicate that although a chemo benefit exists in the 16-to-25 recurrence score group, it may be due to hormonal castration instead of direct anti-cancer or anti-metastatic action. As a result, Oncotype DX, in combination with clinical risk factors, "could identify premenopausal women with higher clinical risk who may benefit from ovarian function suppression and more aggressive anti-estrogen therapy," instead of chemo, he said in a statement.

However, experts reacting to the conference presentation and commenters to the NEJM paper cautioned that this aspect of the analysis was more speculative than definitive.

"The interaction between recurrence score and age was exploratory … [and] whether these women would have received similar benefits from ovarian suppression [with endocrine therapy] instead of chemo-endocrine therapy … needs to be interpreted with caution," said Johns Hopkins breast oncologist Vered Stearns during her discussion of the TAILORx data, though she added that indirect evidence from other studies does suggest that this may be the case.

Discussing the results in a separate ASCO session, Dana Farber oncologist Harold Burstein said that his own interpretation is that the data indicate that "nearly all, if not all the benefit [seen with chemotherapy in low-risk women] is due to endocrine effects."

However, the exploratory analysis didn't convince everyone. In a Q&A session following Burstein's discussion, Jonas Bergh from Sweden's Karolinska Institute challenged Burstein, saying that he was intrigued by the NEJM update, but that both Burstein and Sparano made a claim "with no evidence" that if the women in the trial had received ovarian ablation, "it would not have been needed to offer them chemotherapy."

"This is not evidence-based medicine," Bergh said. "It’s a thoughtful idea but we don’t have data on the level of [prospective studies]."

Precision medicine, by definition, aims to identify the best treatment approaches for patients according to their clinical and molecular characteristics. But as seen with this latest analysis, the intersections between molecular and clinical factors and how they impact patient care aren't always neatly defined.

"The promise of 'precision' medicine has collided with the rather messier world of using all available evidence to try and make educated guesses to improve patient outcomes," David Hunter and Dan Longo from the University of Oxford wrote in a commentary appearing alongside Sparano' TAILORx publication last week.

According to Hunter and Longo, the complexity of the new TAILORx results reflects a "principal tension in modern medical data science."  

For the clinic, distinguishing between results that warrant a change in practice and those that do not cannot be a 'precise' process, even in the molecular era, Longo and Hunter wrote. "Evidence synthesis, clinical judgment, and patient preferences all factor in."

"If we insist on evidence from randomized trials, we will rarely have it, and to the extent we have it, we will have it only for groups of patients who are somewhat similar … [so] physicians and patients will have to face substantial uncertainty, and 'educated guesses' informed by multiple sources of evidence as well as by clinical acumen will continue to be necessary even in the age of precision medicine," they argued.

Asked during a conference session how she thinks the new TAILORx conclusions may impact conversations with younger breast cancer patients, MD Anderson medical oncologist Jennifer Keating Litton echoed this sentiment, saying that "this is where [we] go back to the art of medicine."

While risk is quantified with distinct cutoffs in clinical trials, Keating acknowledged that patients in the real world may have an entirely different calculation of risk. For that reason, she often sits with patients and goes through the data in detail. "A two percent risk may be very different for one person than another," she said.

Guiding extended endocrine therapy

Alongside the issue of how to use molecular assays in younger women, oncologists recently cited a need to resolve whether molecular tests can help identify women who need extended endocrine therapy.

A second presentation at the meeting represented a significant milestone in this area, shoring up evidence for Biotheranostics' Breast Cancer Index test in predicting which women with early-stage, hormone receptor positive tumors stand to benefit from extended endocrine therapy, and which women can stick to just five years of treatment.

Investigators reported an analysis of 583 patients with node-positive disease from the international Translational-aTTom study (Trans-aTTom), concluding that the BCI test effectively stratified patients, distinguishing the 49 percent who showed a statistically significant benefit of 10.2 percent with 10 years of tamoxifen from the 51 percent of patients who did not show a statistically significant benefit from treatment beyond five years.

Although other test providers in the space have said they are exploring use of their assays for guiding extended endocrine therapy, BCI is the only test that has collected this type of comprehensive data so far.

During her discussion of the data at ASCO last week, Johns Hopkins' Vered Stearns said that the analysis of BCI in the Trans-aTTom study does provide some good evidence that Biotheranostics' test can inform therapy decisions and reduce overtreatment.

"However," she said, "before I use this assay in my clinic, I'd like to see the full study results, and ideally, for validation, another study with similar treatment and duration" to meet a higher bar of evidence.

During a Q&A session following the reports from both the Oncotype DX and BCI studies, a meeting attendee from France asked about the clinical implications of having two (if not more) tests that might inform different aspects of shared decision-making for the same patient.

Oncotype DX may help guide the decision on whether to use chemotherapy, but not the question of how long to prescribe endocrine therapy. In contrast, the BCI test can contribute to the latter decision, but not the former.

John Bartlett, program director of diagnostic development at the Ontario Institute for Cancer Research, who presented the Trans-aTTom results, suggested a two-stage approach. "You would first look at the chemosensitivity upfront at diagnosis and decide whether to use chemotherapy for your patients. And then, subsequently, look at whether to extend endocrine therapy with a marker that predicts benefit at that stage," he said.

But the attendee countered that this means doing two genomic tests, something that he could see irking regulators and payors, if not in the US, then in other healthcare systems like France's.

Daniel Hayes, clinical director of the breast oncology program at the University of Michigan Comprehensive Cancer Center, also highlighted during the Q&A that the ASCO tumor guidelines panel "strongly recommends that if you are going to use a genomic test, [that you] just get one."

"Pick the one you like and stick with it. Don’t get two or three in the same patient," he said. "I guarantee you'll get different results, and if you do, please don’t send an email to me."

In their NEJM commentary on Sparano's TAILORx report, Longo and Hunter highlighted that recent head to head comparisons — like a JAMA analysis last year led by investigators at Queen Mary University in London — found differences in risk classification and prognostic ability across available commercial assays, "particularly for late recurrence."

Genomic Health's test "dates from the early days of gene-expression analysis in tumors more than 15 years ago," they added. As a result, it "seems likely" that new approaches incorporating larger-scale gene-expression data, genomic copy-number alterations, and epigenetic data may "lead to an at least incrementally superior panel," they added.

However, they wrote, "the introduction of new panels runs into the market dominance of an assay [Oncotype DX] that has been established as clinically useful through many trials, including the current one."

"In practice … barriers to innovation are high," they added.

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