The year ahead could be a provocative year in breast cancer treatment and research, according to several breast cancer specialists polled by The ASCO Post during the 2010 San Antonio Breast Cancer Symposium. We asked them to comment on emerging issues that should be on the oncologist's radar in 2011.

New Pathways Delineated

In 2011, scientists expect to better understand oncogenic pathways that are revealing themselves to be important in breast cancer, much of this knowledge coming as a result of the tissue banking that is essentially routine in the current clinical trial setting.

"We have seen a saturation of a certain set of analyses for endocrine therapy and chemotherapy, and we are now looking for the next wave of targeted treatments to come along," said Harold Burstein, MD, of Dana-Farber Cancer Institute, Boston. "Whether that will be inhibitors of PI3-kinase, mTOR, insulin growth factor receptor-1, or others… we can expect new pathways to open up this field again." Drugs targeting these pathways are in early-phase development, and the hope is that associated biomarker development "will be provocative and get oncologists excited for the next generation of breast cancer agents."

Triple-negative Breast Cancer Demystified

Triple-negative breast cancer has stymied clinicians and scientists for the past several years. Current efforts are directed at drilling down to the molecular level of this subtype of breast cancer. "We are trying to understand the heterogeneity of triple-negative breast cancer, and there are big questions," said Lisa Carey, MD, of the University of North Carolina, Chapel Hill, who has conducted seminal research in this field. "Much effort is going into determining how these tumors will behave, even when stratified within a clinically identifiable subset. We know that some of these patients do very well, while others do not. Clearly, multiple factors affect sensitivity to existing drugs, and these are currently are not well understood. With triple-negative breast cancer, it seems the more we know, the more we discover what we don't know.

"Clinically, one of the main questions relates to the PARP inhibitor story,"  Dr. Carey commented. (Dr. Carey discusses the PARP inhibitor story in an upcoming issue of The ASCO Post.)

Personalization of Endocrine Therapy

One of the problems with endocrine therapy is the development of side effects that many patients find intolerable. "The aromatase inhibitors are not just used for endocrine therapy, but they have become the backbone for novel targeted therapies as well, so they are increasingly important. We are trying to understand the pharmacologic differences within this class of agents that interact with patient factors to produce toxicities, especially arthralgias and bone metabolism changes," said Paul Goss, MD, PhD, professor of medicine at Harvard Medical School, Boston, and Avon Foundation senior scholar. Based on his own experience with the MA.27 trial, which has the largest tumor tissue repository among breast cancer trials, he noted that the era of personalized endocrine therapy is near. For example, four genetic polymorphisms have recently been shown to predispose to musculoskeletal side effects. Such information about tumor signatures will allow oncologists to more safely prescribe these agents, he said. "Advances in personalized medicine will come out of MA.27," Dr. Goss commented, "and you will see many papers on this in 2011 and beyond."

Also in 2011, the oncology community will learn whether exemestane can prevent breast cancer, added Dr. Goss, who is heading up the NCIC CTG MAP3 trial. The study will follow more than 4,500 postmenopausal women with mildly elevated breast cancer risk receiving exemestane or placebo. Investigators hope to see as much as a two-thirds reduction in the incidence of breast cancer with exemestane treatment and will present their findings early in 2011. "This study is a vehicle to see if aromatase inhibitors are as powerful in preventing breast cancer as we think they are," he said.

Biomarkers and Drug Development: Not as Encouraging

The need for biomarkers in breast cancer research has been a rallying cry among investigators for several years. According to David Miles, MD, of Mount Vernon Cancer Centre, Northwood, Middlesex, UK, who was instrumental in trials of bevacizumab (Avastin), finding useful biomarkers and applying them to drug development may be a more daunting challenge than many realize.

"We have global problems in drug development. We are now at a point where developing drugs and making money at the end of the process is almost impossible," Dr. Miles suggested. There is huge variability in gene expression within tumor specimens, he said, "and when you multiply this by the many statistical problems, you end up questioning whether we can even do biomarker trials at all. Every trial now has its translational studies, and the expectation is that somehow these will produce meaningful results. But the bottom line is there are a lot of false-positives, which is a problem. It's discouraging."

Drug development timelines also impede progress in the search for biomarkers. "Drug development is where we are hitting a wall. Even when we get an interesting result in terms of a potential biomarker, the only way to nail it is to prospectively validate the biomarker in an additional clinical trial. By then, you've done your registration trial, and the company may feel there is no point in investing in a program that will use up too much of the remaining patent life," he pointed out. "We need to be more intelligent about the markers we expect to prove useful, and we must have more collaboration among research centers. We need big patient populations, and, therefore, we must study these questions on a global level."

Next-generation Sequencing Will Characterize Cancer Cells

Knowledge of DNA sequences has become indispensable for basic cancer research, and rapid sequencing was instrumental in deciphering the human genome. Now, so-called next-generation sequencing is unraveling the molecular mysteries of breast cancer.

"I am really excited about the advent and utility of next-generation sequence technology applied to breast cancer and tumor biology in general," said Mark Pegram, MD, who spearheaded many of the early lab studies of trastuzumab (Herceptin). "At the University of Miami we are participating in the NCI's Human Tumor Genome Atlas, a campaign that will sequence some 1,000 breast tumors over the next couple of years. This will enhance our knowledge base about molecular alterations in breast cancer and, most importantly, in the subtypes of breast cancer."

His lab is also using next-generation sequencing technology to interrogate other biologic processes in breast cancer, one of which is drug resistance in cell lines. Through repeated selection pressure, Dr. Pegram and colleagues have generated cell lines that are resistant to trastuzumab, lapatinib (Tykerb), and the combination of the two, as well as to antibody-dependent cellular cytotoxicity with trastuzumab. They are sequencing all the nucleotides in these cell lines. "We will characterize the resistant cell lines and find out whether the resistance is associated with new genetic alterations," he said. Preliminary data are expected in 2011.

New Drugs Will Target Bone

The ability to prevent skeletal complications, and even bone metastases, does not stop with the bisphosphonates or denosumab (Prolia, Xgeva). New drugs in the pipeline will target different pathways in bone health and may provide additional options for patients with bone metastases or bone loss in the future, according to Alison Stopeck, MD, of the Arizona Cancer Center, Tucson, who spearheaded research on denosumab. Key compounds in this regard are Src inhibitors and drugs directed against the Wnt inhibitor Dickkopf-1 (DKK1). Anti-DKK1 agents suppress tumor-induced bone resorption in murine models of multiple myeloma, and therefore, are being evaluated for the treatment of bone resorption in other malignant bone diseases. "They will have different efficacy and toxicity profiles, and we may be able to use them in synergy with our current agents to greatly improve bone protection," Dr. Stopeck said.

Changing Times for Community Oncologists

The next year will be a time of greater practice consolidation among oncologists, as physicians accept that "more and more practices cannot survive on declining reimbursement," said Lee Schwartzberg, MD, of the West Clinic in Memphis, Tennessee, who has long been active in community oncology affairs. "In 2011 we will see a huge move toward practices discussing ways to partner with hospitals-either selling their practices outright to hospitals, or making co-management arrangements or professional services agreements. All these activities will accelerate."

But other changes have a more positive ring: greater movement toward electronic technology and ultimately more measurement of quality parameters. This will benefit patients and will be viewed positively from an economic standpoint. "Payers and Medicare are increasingly looking for value-based oncology," he said. ■