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Divide-and-conquer strategy drives breast cancer breakthroughs

Breast cancer specialist Paula Ryan and basic scientist Leif Ellisen, of MGH, are co-investigators on a phase II trial of cisplatin for triple negative breast cancer.

Breast cancer specialist Paula Ryan and basic scientist Leif Ellisen, of MGH, are co-investigators on a phase II trial of cisplatin for triple negative breast cancer. (Photograph by Joshua Touster)

Pulling a page from ancient Rome’s military handbook, investigators in the DF/HCC Breast Cancer Program are deploying a divide-and-conquer strategy in the battle against breast cancer. Rather than mounting a one-strike-fits-all assault against a heterogeneous enemy, scientists are dividing the enemy into smaller, more homogeneous adversaries — whose unique vulnerabilities can be exploited with greater tactical precision.  

“Breast cancer is not just one disease, but a diversity of distinct entities,” says program leader J. Dirk Iglehart, MD (DFCI). “This realization is changing the way we do translational science.” Based on genetic data, the program classifies life-threatening breast tumors into three broad subtypes: hormone-receptor positive, HER2-positive, and triple negative. Clinical trials initiated within DF/HCC are now testing an array of innovative subtype-specific therapies — and applying them preoperatively, when safe and feasible — resulting in some profound improvements, says Iglehart.
Overcoming resistance in receptor-positive disease

Hormone receptor-positive breast cancer accounts for approximately 60 percent of all breast tumors. The hallmark of these tumors is a high number of estrogen receptors (ER) and/or progesterone receptors (PgR), which stimulate cell growth when bound by these hormones. Their hormone dependency renders these tumors vulnerable to targeted endocrine therapies including tamoxifen and aromatase inhibitors that deprive tumors of estrogen. But although aromatase inhibition (AI) has demonstrated “a modest disease-free survival benefit” compared with tamoxifen, explains breast cancer specialist Paula Ryan, MD, PhD (MGH), resistance remains a critical problem. Thus she and co-investigator Paul Goss, PhD (MGH) — an international expert on endocrine therapy and leader of the Breast Cancer Program — have embarked on several novel studies to thwart the tumor’s development of resistance and improve patients’ progression-free survival.

In one study, investigators are attempting to suspend or delay resistance by administering the aromatase inhibitor letrozole intermittently. This on-off strategy is premised on the observation that as tumor cells become chronically estrogen-deprived, they develop hypersensitivity to the hormone. Just how this happens is unclear, notes Ryan. “When all estrogen-sensitive cells in the tumor are eliminated, that may leave only drug-resistant clones,” she hypothesizes. “If we interrupt AI, we hope to retain some intratumoral heterogeneity,” which may control the growth of drug-resistant cells.

A unique aspect of this study is the use of CA 15-3 as a tumor marker to help determine, in combination with scans and monthly clinical evaluation, when to make changes in therapy. “Once we’ve seen that patients have responded to AI, we stop their therapy and watch the marker,” explains Ryan. “If it goes up 25 percent, we put them back on the drug.” This process is repeated in a cyclical fashion, using the tumor marker to dictate when to halt or reintroduce letrozole.

In another trial, Ryan and Goss are attacking the problem of endocrine resistance by testing one of the antibodies to the insulin-like growth factor 1 receptor (IGF-1R) in combination with the aromatase inhibitor exemestane, compared with exemestane alone. Underlying this study is the hypothesis of “crosstalk” between the estrogen receptor and IGF-1R pathways as a possible mechanism of resistance. The primary objective of the study — the first to evaluate an IGF-1R antibody in patients with breast cancer — is to see whether blocking crosstalk increases progression-free survival in women with metastatic hormone-positive disease, which has no cure.

Armed antibodies and other targeted treatments for HER2-positive breast cancer

About 20 percent of breast tumors overexpress the human epidermal growth factor receptor 2 (HER2) gene. Until the emergence of HER2-targeted therapies a decade ago, these tumors were very difficult to treat, says Eric Winer, MD director of the Breast Oncology Center at DFCI and one of the first investigators to conduct preoperative trials using the HER2 antibody trastuzumab (Herceptin) for early-stage HER2-positive breast cancer. Herceptin remains a remarkable drug, says Winer, but in women with metastatic disease, the cancer almost always finds a way to grow in spite of continued Herceptin treatment. And scientists do not fully understand its mechanisms of resistance. “In some patients, the disease is entirely refractory to the drug; in other patients, it continues to exert an effect but the cancer finds a path around the blockade.” Moreover, in about a third of patients with advanced disease, brain metastases develop despite treatment, largely because Herceptin does not reach the brain, explains Winer. His research group was the first to describe this problem and the first to conduct studies of targeted treatment with lapatinib — a dual EGFR and HER2 inhibitor that, unlike Herceptin, may cross the blood brain barrier — to overcome the problem.

Winer and colleagues are currently heading a number of trials in patients with advanced HER2 disease whose cancer has progressed while on trastuzumab. One novel approach to overcoming resistance is the T-DM1 trial, in which patients receive a first-in-class “armed antibody” — a conjugate of trastuzumab with the potent chemotherapy drug maytansinoid. Trastuzumab serves a dual function, delivering the lethal drug directly to HER2+ cancer cells and decreasing HER2 signaling. “So far, the conjugate has been well tolerated and associated with a remarkable amount of activity,” notes Winer. In all these studies, investigators are also correlating what they see in the tumor on a molecular level with the response seen in the patient.
Turning on death genes in triple negative tumors

Neither HER2-targeted therapies nor aromatase inhibitors are effective against the third broad subtype of breast cancer, a group of aggressive tumors that lack expression of ER, PgR, and HER2. Compared with other breast cancer subtypes, these “triple negative” tumors — of which 80 percent are basal-like cancers — have had a poor prognosis. But recent discoveries from the laboratories of Leif Ellisen, MD, PhD (MGH), David Livingston, MD (DFCI), Andrea Richardson, MD, PhD (BWH), and others are now yielding promising treatments for these refractory cancers.

Because up to 90 percent of women with BRCA1-associated breast cancer have the triple negative subtype, investigators wondered whether the tumors that harbor BRCA1 mutations might share certain molecular features with other triple negative tumors that do not. Indeed, the gene expression profiles of a subset of triple negative tumors revealed high levels of p63, a master regulator of normal breast development that binds tightly to p73 and prevents it from inducing apoptosis. “We found that most BRCA1-associated cell lines had this p63/p73 signature, but only about a third of the other triple negatives had it,” says Ellisen, who is co-director of the MGH Translational Research Lab where the genetic analyses were conducted. Surprisingly, his lab also showed that high expression of p63 and p73 in the cell confers sensitivity to platinum — a cytotoxic agent rarely used in breast cancer — which effectively turns on “death genes” by activating p73 and inhibiting p63.

These and other data led Judy Garber, MD, MPH, director of the Cancer Risk and Prevention Clinic at DFCI, to propose a bold experiment: the first preoperative clinical trial of cisplatin in women with recently diagnosed triple negative breast cancer. Results of the trial were startling. “Of 28 women receiving treatment, 22 percent had complete response and another 25 percent had significant shrinkage,” says Garber, the principal investigator.

“When we looked at the genetic signature in Judy’s trial,” adds Ellisen, “we found that patients who were p63/p73 positive were about five times more likely to have a complete pathologic response from single-agent cisplatin than patients who were p63/p73 negative.” The success of the trial spawned a new cisplatin study in the metastatic setting to assess response rate and evaluate the p63/p73 signature as a predictive biomarker of response.

“We’ve been able to conduct these clinical trials because of discoveries in the lab,” says Garber. “Now, from our clinical data, scientists can go back to the bench and ask new questions. We’re really in this together.”

—Lonnie Christiansen