Gradishar Provides Insight into New Breast Cancer Treatments

William J. Gradishar, MD

New treatments for HER2-positive (HER2+) tumors have dominated media coverage of breast cancer breakthroughs over the past year, but William Gradishar sees promise on many fronts.

Trials and analysis continue to hone our understanding of how and when mTOR inhibitors such as everolimus (Afinitor) counter resistance to aromatase inhibitors in metastatic cancer.

New trials, meanwhile, are beginning to explore whether the drug produces significant benefits when used as an adjuvant treatment.

Another possible tool against endocrine resistance is the novel HDAC inhibitor entinostat, which received the FDA’s Breakthrough Therapy designation after one phase II study of metastatic ER-positive cancer showed that it nearly doubled progression-free survival (PFS) over placebo.

A second Breakthrough Drug candidate that, according to Gradishar, merits attention is palbociclib, an inhibitor of cyclin-dependent kinases 4 and 6. Preliminary results from a phase II palbociclib trial showed that the drug, when used with letrozole (Femara), more than tripled PFS over letrozole alone.

“There’s also new hope in areas of research that had nearly been left for dead,” Gradishar said. “The failures of bevacizumab (Avastin) dulled interest in angiogenesis, but trials of new compounds suggest angiogenesis may have its use. Likewise, there’s exciting new research on PARP inhibitors—used with assays to choose patients who will benefit—in triple-negative cancers.”

As for HER2+ tumors, the news has indeed been good enough to justify a spate of recent coverage.

In one phase III trial of 417 women, neoadjuvant treatment of pertuzumab (Perjeta) in combination with trastuzumab and docetaxel produced pathological complete responses in 39.3% of patients—nearly twice the number who responded similarly to the existing standard of care, trastuzumab (Herceptin) plus docetaxel.

The FDA responded by awarding the treatment accelerated approval.

“The numbers really are very significant, which is why the FDA acted so quickly,” Gradishar said, “but clinicians should keep an eye out for the final study analyses, which should provide more clarity on which patients should receive this treatment and when.”

Pertuzumab is the first HER dimerization inhibitor to win FDA approval, but physicians who treat HER2+ tumors may soon have other options. Several similar monoclonal antibodies have reached the final stages of testing.

Another potential advance against HER2+ cancers is the mTOR inhibitor everolimus, which demonstrated significant ability to overcome trastuzumab resistance in 572 BOLERO-3 trial patients.

When added to trastuzumab and vinorelbine, everolimus reduced the risk of progression or death by 22% compared with placebo, giving patients, on average, about an extra month of life.

“The truly exciting thing isn’t the result of any study or the promise of any one medication,” Gradishar said. “It’s the sheer number of studies showing significant clinical gains from new compounds or new ways of using or combining existing compounds.”

William J. Gradishar, MD, is the Betsy Bramsen Professor of Breast Oncology at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois.