Gene Sequencing Helps Target Therapies for Metastatic Breast Cancer

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By Annette M. Boyle

Maren Scheuner, MD

Maren Scheuner, MD

DURHAM, NC — Women initially diagnosed with metastatic breast cancer have only a 23% overall five-year survival rate — and will spend most of their lives battling their cancer with a series of chemotherapies that might not work or might stop working in a few months.

Now, advances in genomic understanding of breast cancer tumors bring hope for more effective treatments that target specific mutations and reduce exposure to therapies that might do more harm than good.

“We have a panel now that looks for 18 genes associated with relatively high risk for developing breast cancer,” said Maren Scheuner, MD, chief of the division of medical genetics at the VA Greater Los Angeles Healthcare System and director of clinical genetic services for VISN 22. That analysis can help patients understand their inherited predisposition to develop breast cancer and encourage them to take control of environmental factors that might increase it.

The VA’s Million Veteran Program is making huge strides toward better understanding of how genes affect health and what familial or environmental factors may activate particular diseases. With 240,000 veterans now enrolled, the Million Veteran Program already exceeds the enrollment numbers of any previous VA research program.

“It will bring us closer to realizing personalized medicine — an approach that helps us better understand why some individuals develop certain conditions and diseases and others do not; aid in the early detection of post-deployment health issues; and lead to customized treatments,” said Joel Kupersmith, MD, a former VA chief research and development officer.

The standard panel analyzes the genes with which a person is born, but emerging research looks at the “genetic changes in the DNA that allows cancer cells to take on a life of their own,” Scheuner added. “Using next-generation sequencing, we can look at hundreds of thousands to millions of fragments of DNA for variations from normal cells. Sampling tumors allows us to see how they have evolved over time and better understand what genes are activated or suppressed.”

While personalization of treatment for metastatic breast cancer might soon be feasible, more work needs to be done to develop targeted therapies. A recent study (SAFIRO1), which tested all of the DNA in the genome of breast cancer cells, found that less than half of the participants had genetic alterations for which current treatments exist. Nearly 40% had less-common genetic variants that have not yet been targeted for treatment. 1

The researchers obtained biopsy samples from 407 women and used comparative genomic hybridization (CGH) array and Sanger sequencing on PIK3CA and AKT1 on 67% and 70% of samples, respectively.

According to the results published in the Lancet Oncology, the French researchers found targetable genomic alterations in 46% of patients (195), primarily in PIK3CA (25%), CCND1 (19%) and FGFR1 (13%).

In an accompanying editorial, Charles Swanton, MD, PhD, of the Cancer Research UK London Research Institute noted the work that remains to translate genomic research into clinical results. “In view of the challenges highlighted by SAFIR01, efforts to accelerate genomic analyses for personalized medicine must continue to be embedded within the context of clinical trials, and integrated with scientific and clinical collaborative structures to deliver measurable benefits to patients. The findings of SAFIR01 represent an important first step on this journey.” 2

One of the first genetically targeted therapies, trastuzumab has been used for years to treat early-stage and metastatic breast cancer characterized by overexpression of human epidermal growth factor receptor 2 (HER2). Now, “we’re looking at additional targets, specific genetic changes in tumors that can be treated,” Scheuner said. “It may be that only a handful of these changes really make a difference, but we need more research to tell us which are the key determinates in cancer progression.”

A new paradigm for metastatic breast cancer treatment is developing as the technique for genomic sequencing has improved, added Michael Kelley, MD, VA national program director of oncology. The goal of future research “is to identify the specific genetic alterations associated with a particular drug that leads to great response,” but that’s challenging as only a minority of patients have tumors that can be targeted.

Genomic sequencing is rapidly moving beyond currently available therapies. “There are many mutations that we’ve known about for a long time, but we don’t have drugs that address them. About 50% of breast cancer patients have overexpression of P53. If we could target that specifically, it would be a major advance in treatment,” Kelley said.

Some new drugs hold promise for more personalized treatment of late-stage breast cancer. At the American Association for Cancer Research annual meeting in April, researchers presented preliminary results of for two new therapeutic agents. The oral drug bemaciclib, a cyclin-dependent kinases 4 and 6 (CDK-4/6) inhibitor, showed a 61% clinical benefit rate in patients with hormone receptor positive metastatic breast cancer in a Phase 1 trial. In patients with metastatic luminal A breast cancer, another CDK-4/6 inhibitor, palbociclib, combined with letrozole showed a median progression free survival of 26.1 months vs. 5.7 months on letrozole alone, or a 70% reduction in the progression hazard. 3, 4

With or without with targeted therapies, metastatic breast cancer patients face a difficult road.

“Even when we have great response to a drug, it typically doesn’t lead to long-term survival because the cells become resistant,” Kelley added. Consequently, clinicians and patients will likely continue to rely on a progression of treatments that include surgery, radiation, hormonal therapies and cytotoxic agents as well as increasingly personalized therapies that address specific features of tumors as they evolve.

1 Andre F, Bachelot T, Commo F, Campone M, Arnedos M, et al. Comparative genomic hybridization array and DNA sequencing to direct treatment of metastatic breast cancer: a multicenter, prospective trial (SAFIRO1/UNICANCER). The Lancet Oncology; 15(3):267-274. March 2014.

2 Swanton C. SAFIR01: Steps toward precision treatment in breast cancer. Lancet Oncology; 15(3):242-243. March 2014.

3 Patnaik A, et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. AACR 2014; Abstract CT232.

4 Finn RS, et al. Final results of a randomized, phase II study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole versus letrozole alone for first-line treatment of ER+, HER- advanced breast cancer (PALOMA1/TRIO18). AACR 2014; Abstract CT101.

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