Cancer and non-cancer drugs make headway as chemopreventive agents

SAN ANTONIO-Options for breast cancer prevention range from “noninvasive” lifestyle changes (diet, nutrition, exercise) to more radical surgical approaches. In between are preventive medications that are currently under investigation in small clinical trials, said Judy Garber, MD, director of the cancer risk and prevention program at the Dana-Farber Cancer Institute in Boston.

There are currently two pharmacologic agents that are currently approved for breast cancer prevention: Tamoxifen and raloxifene (Evista). During an SABCS 2009 educational session, Dr. Garber outlined some of the advances in chemoprevention of ER-negative/HER2-positive breast cancers.

Lapatinib as risk-reducing agent

Lapatinib (Tykerb) has proved itself in breast cancer treatment, but it may also modulate biomarkers and lead to the suppression of tumor formation. The LAPIS trial is currently recruiting patients and will evaluate whether lapatinib can be used therapeutically in women with ductal carcinoma in situ (DCIS) that is either HER2-positive or EGFR-positive.

“[LAPIS] is a short-exposure trial, and short-exposure trials have a big advantage,” Dr. Garber said. “Here are women who’ve had a biopsy and they are going to have surgery so you have the opportunity to get tissue. What you need to do is convince these women that in the short time that they have to wait for surgery, it’s OK for them to take [lapatinib].”

LAPIS will be led by Powel Brown, MD, PhD, from M.D. Anderson Cancer Center in Houston. Dr. Brown moderated the SABCS educational session.

Metformin: All-around anti-cancer agent

Pharmacoepidemiology studies can yield data on cancer risk reduction. One example is the connection between metformin, a diabetes drug, and cancer risk. Dr. Garber cited a 2005 pilot study out of Scotland that found that patients with type 2 diabetes who were receiving metformin seemed to have a reduced risk of cancer (BMJ 330:1304-1305, 2005).

Also, a separate study indicated that the rate of pathologic complete response was higher in diabetic patients with breast cancer who were receiving metformin and neoadjuvant chemotherapy than in diabetic patients who were not taking metformin (J Clin Oncol 27:3297-3302, 2009).

Finally, Italian investigators have undertaken a presurgical, randomized, phase II biomarker trial to determine the activity of metformin on tumor cell proliferation in breast cancer patients (Cancer Epidemiol Biomarkers Prev 18:701-705, 2009).

Pamela J. Goodwin, MD, is currently leading a large-scale, phase III trial of metformin in the adjuvant breast cancer setting. The MA.32 trial will evaluate the effects of metformin on breast cancer outcomes, including recurrence and death, in patients who are randomized to metformin or placebo after the completion of adjuvant therapy (J Clin Oncol 27:3271-3273, 2009).

One of the theories behind the biological mechanism of metformin is that the drug affects insulin levels. Insulin, and insulinlike growth factor (IGF), have been associated with elevated cancer risk, Dr. Garber pointed out.

COX2 and statins

“COX2 has received a lot of attention” said Dr. Garber. “COX2, as a molecule, has been critical in the evolution of breast cancer, although we’ve had issues with COX2 inhibitors. But the possibility that COX2 could interfere with breast cancer development has been known for some time.”

She cited an ASCO 2007 presentation of a phase II prevention trial of celecoxib (Celebrex) in women at increased risk for breast cancer. Lead author Banu Arun, MD, and colleagues found a significant modulation of IGF binding protein-1 levels within six months of celecoxib treatment in high-risk women. They determined that the modulation of the biomarker, and an acceptable level of adverse effects, supported the continued evaluation of celecoxib for breast cancer prevention (abstract 1501).

As for statins, they are used by a larger portion of the population, but their role in the reduction of breast cancer risk has been uneven, Dr. Garber said.

A study out of Kaiser-Permanente in Oakland, Calif., found that breast cancer patients with exposure to statins had proportionately fewer ER-negative/progesterone receptor-negative tumors that were of a lower grade and stage. Although the authors could not show that statins directly affected the cancer, they did state that statin use influenced tumor phenotype (Cancer Epidemiol Biomarkers Prev 17:1028-1033, 2008).

More recently, Laura Esserman, MD, MBA, and colleagues found that women with a diagnosis of DCIS or other stage I breast cancer had reduced tumor proliferation and increased apoptosis when treated with fluvastatin. “These results support further evaluation of statins as chemoprevention for ER-negative high-grade breast cancers,” they stated (Breast Cancer Res Treat online, August 29, 2009).