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SABCS at 40: Though nobody's perfect, no midlife crisis

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By Anette Breindl
Senior Science Editor

SAN ANTONIO – One of the most anticipated presentations on the first day of the 2017 San Antonio Breast Cancer Symposium (SABCS) was the B-47 study, which investigated the use of adjuvant Herceptin (trastuzumab, Roche Holding AG) in patients with low HER2 expression.

Superficially, it was an unqualified failure.

Presenter Louis Fehrenbacher, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo Medical Center, did not mince words on his conclusions slide.

"The primary objective of improving IDFS" – invasive disease-free survival – "was not met. None of the secondary endpoints were met. No trends of efficacy were seen."

But B-47 addressed, and illustrated, many of the issues that both the oncology and the broader research communities are currently wrestling with: the importance of understanding biomarkers, and of standardizing their measurement; the importance of preventing overtreatment, both from a clinical and from a cost perspective; and the importance of presenting negative data.

The B-47 study was conducted because of a surprising finding in the B-31 and N9831 studies, presented in 2005, that showed large gains in disease-free survival for women with HER2-overexpressing breast cancers who were treated with Herceptin in addition to chemotherapy.

Some women in those studies, however, were included due to a measurement error, and on replication, did not have high levels of HER2 expression.

In the original studies, though, it didn't seem to matter.

Women with low HER2 levels at confirmatory testing (which was performed centrally and presumed to be more accurate than the original local testing) got just as much benefit from Herceptin as those with confirmed high expression levels, prompting the B-47 study.

Fehrenbacher told reporters that the discrepancy between the two studies surprised him, and that "the retrospective outcome differences between local-tested HER2-positive and central-tested HER2-low patients identified in two major adjuvant trials are not readily explained" by the new study.

The B-47 trial is an example of ongoing challenges with biomarkers, an area where great promise meets lack of everything from biological understanding to standardization. (See BioWorld Today, Dec. 7, 2016, and June 5, 2017.)

It also shows how far clinical oncology has come. Round anniversaries lend themselves to looking back as well as forward, and the 40th was no exception.

SABCS at 40

At the opening session, Richard Pazdur, director of the Oncology Center of Excellence at the FDA, gave an overview of past accomplishments as well as his predictions for future directions.

Pazdur shared his own expectations of yesteryear with the audience – expectations that have been almost comically unmet.

In the late 1970s, he said, his predictions were that in 2017, the vast majority of patients with cancer would be treated at academic medical centers, and every patient would be enrolled on a clinical trial.

He also thought that the drugs used in those trials would be developed mainly by the National Cancer Institute, because "commercial pharmaceutical companies would have little to no interest in oncology."

It's easy to chuckle at those expectations, now that oncology is the single most active area of drug development for the pharmaceutical activity. Oncology accounts for 30 to 40 percent of all drug development activity, and a whopping 50 percent of all breakthrough drugs.

But given the state of cancer drugs in the 1970s, they were not unreasonable at the time.

Cancer itself carried a stigma, as did the drugs used to treat it, which were highly toxic and used for short time periods "a model that would not be viable for the pharmaceutical industry" from either a public relations or a financial standpoint.

Pazdur identified the turning point as the 2001 approval of Gleevec (imatinib) for chronic myelogenous myeloma.

Prior to the advent of Gleevec, Pazdur said, oncology drug development resembled spinning a roulette wheel.

"Drugs would be discovered on the basis of antiproliferative activity, tested in phase I, and then developed in a wide variety of tumor types without compelling rationale," either because there was some glimpse of activity or on the basis of economic considerations, in large indications.

Gleevec was the first drug, he said, that was not developed through "the proverbial needle in the haystack approach." Instead, it demonstrated a tailored approach based on a deep molecular understanding of the disease it was targeting, and provided a framework for developing other drugs via the same approach.

Given the progress that has been made since 2001, Gleevec already seems somewhat Model T-like. Current goals for oncology include developing treatment strategies that can prevent or overcome resistance to targeted treatment, and diagnosis that is both more precise and more comprehensive, allowing patient stratification not just by their tumor drivers but also by their own genetic makeup and other factors pertinent to their treatment response. The advent of tumor immunotherapy has also transformed the field.

Both Pazdur and Kent Osborne, professor of medicine and molecular and cellular biology at the Baylor College of Medicine and the SABCS co-director, expressed hope that precision medicine will be a way to achieve further improvements in treatment.

"You're probably tired of the term," Osborne told the audience in his welcoming remarks. "I'm getting a little tired of it."

Still, the phrase captures the idea that science is the critical underpinning of improving medicine – not least because precision medicine enables the de-escalation of treatment in patients who will not benefit, as was the case in the B-47 trial.