WASHINGTON, DC—The 2008 Breast Cancer Symposium here showcased new approaches to treating and preventing breast cancer, including combining endocrine therapy with an anti-angiogenesis drug, and lowering insulin levels in women with hyperinsulinemia.
The symposium was cosponsored by the American Society of Breast Disease, American Society of Breast Surgeons, American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, National Consortium of Breast Centers, and Society of Surgical Oncology.
Recently it was found that anti-vascular endothelial growth factor (VEGF) therapy improves the effectiveness of chemotherapy when the two treatments are combined, noted Maura N. Dickler, MD, Assistant Professor of Medicine at Memorial Sloan-Kettering Cancer Center. Specifically, she said, the anti-VEGF antibody bevacizumab improves the response rate and prolongs progression-free survival when added to weekly paclitaxel in first-line treatment for patients with metastatic breast cancer.
“We know that anti-VEGF therapy improves chemotherapy, but does it improve endocrine therapy?”
Answering affirmatively, she said that new evidence suggests that anti-angiogenic therapy in combination with endocrine therapy may also be a successful strategy—an approach that will be tested in a proof-of-concept Phase III, randomized, placebo-controlled multicenter trial.
The new trial, which will be led by Cancer and Leukemia Group B, will enroll patients to first-line endocrine therapy (physician's choice of letrozole or tamoxifen) with or without bevacizumab.
Research is showing that estrogen directly affects angiogenesis under both physiologic and pathologic conditions, and the adult endometrial microvascular blood supply “undergoes cyclical, benign angiogenesis under the control of ovarian steroids,” she noted. In addition, preclinical research has shown that estrogen rapidly induces VEGF expression in the rat uterus, and that in breast cancer models, estrogen increases VEGF protein in MCF-7 breast cancer cell lines.
Combining endocrine and anti-angiogenesis therapies has a strong rationale, said Dr. Dickler: Research has shown that in patients with hormone receptor-positive breast cancer, high levels of tumor VEGF lead to a lower response rate to endocrine therapy and shorter progression-free survival compared with low VEGF levels.
She and her colleagues reported preliminary results of a feasibility and safety study of combining bevacizumab and letrozole (2005 San Antonio Breast Cancer Symposium). In that study, 43 women with hormone receptor-positive breast cancer received 2.5 mg of oral letrozole daily and 15 mg/kg of intravenous bevacizumab every three weeks; to date, this combination has been well tolerated, with the most common toxicity being hypertension, Dr. Dickler said. “Anti-VEGF therapy and endocrine therapy are well tolerated in Phase II trials.”
In a related finding, a preliminary Phase II study analysis from Georgetown University's Lombardi Comprehensive Cancer Center of an ongoing Phase I/II trial found that 26% of 27 breast cancer patients taking sorafenib combined with anastrozole had a clinical benefit response.
In that study, led by Deepa Subramaniam, MD, Director of Lombardi's Brain Tumor Center, the participants were postmenopausal patients with metastatic breast cancer whose breast cancer had recurred or progressed while they were taking anastrozole, thought to be because their tumors had become resistant to anti-hormonal therapy. The study measured circulating endothelial cells as an angiogenesis biomarker, and found that a fall in these cells appears to predict response to the combined therapy.
A potential prevention strategy involves targeting insulin and insulin-like growth factors (IGF) as a way to lower the risk of breast cancer in high-risk women or to lower the risk of recurrence in those who have been diagnosed, said Michael Pollak, MD, Professor of Oncology and Medicine at McGill University and Jewish General Hospital in Montreal.
Dr. Pollak said that in the late-1990s his research team and other groups observed from population studies that people with higher levels of circulating IGF-1 had an increased risk of epithelial cancers such as those of the breast, prostate, or colon. Now, evidence is mounting that being overweight or obese—conditions that affect more than 60% of the adult US population—can lead to hyperinsulinemia.
A high body mass index leads to higher levels of IGF-1, and “Higher IGF-1 leads to mammographic density, a known risk factor for breast cancer,” said Dr. Pollak. He cited a study in the September 1 issue of the Journal of Clinical Oncology showing that IGF-1 signaling is implicated in many cancers, including breast cancer.
This study adds to growing evidence that obese patients have higher levels of IGF-1 activity and in some cases, a greater likelihood of aggressive, estrogen receptor-negative breast cancer. An editorial in the same issue of JCO, citing this and other obesity/cancer-related articles in that issue, states, “…a picture is emerging that can not be ignored: there is a growing body of literature that patient weight influences outcome after cancer treatment. How do we, as clinicians, incorporate this information into clinical practice?” The editorial states that weight management should be “a routine component of the multidisciplinary approach to cancer.”
“Emerging evidence that hyperinsulinemia may be involved in the relationship between obesity and cancer mortality suggests that lifestyle and possibly pharmacologic strategies to lower insulin levels in at-risk subjects and/or newly diagnosed cancer patients deserves investigation,” said Dr. Pollak. “Diet and exercise [which lowers insulin levels] may be important.”
He noted that drugs such as metformin, widely used for patients with Type II diabetes, are known to lower insulin and activate AMP kinase, which may activate pathways that block proliferation. In addition, he said, population studies have given rise to an intriguing finding: “an unexpectedly low cancer burden in patients with diabetes on metformin compared with patients with diabetes on other therapies.”
As a result of these research findings, said Dr. Pollak, many new drug compounds exploiting the link between lowering insulin levels and reducing breast cancer risk are now under study. However, while this research is promising, potential toxicities do have to be addressed.
Study findings released at the American Institute of Cancer Research and World Cancer Research Fund international conferences have suggested that in obese people, excess body fat causes greater amounts of IGF-1, estrogen, and other growth factors to be pumped into the bloodstream, thus raising cancer risk. In certain developing countries, borderline malnutrition is giving way to western-style junk food, and with this change in diet breast cancer rates in these countries are rising alarmingly, he said.
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