Tens of thousands of women are having surgery – sometimes even having both breasts removed – to treat a condition that is unlikely to ever become life-threatening. In fact, a recent study concluded that a small, but growing minority of women with the condition – called ductal carcinoma in situ, or DCIS – are choosing to undergo a double mastectomy. That’s despite a lack of evidence for any survival benefit over less invasive surgery. But the fear is little surprise, given what’s unknown about DCIS.
UCSF breast cancer oncologist Shelley Hwang, MD, is bucking this trend toward more invasive treatment. Her clinical research team is investigating whether at least some women with DCIS can safely omit surgery altogether from their treatment. In the course of their studies, the researchers also hope to fill in some of the knowledge gaps surrounding the condition. DCIS looks like cancer. It generally grows as a small collection of cells lining the breast’s milk ducts. But DCIS cells do not behave in the same way as the cells of an invasive breast tumor – pathologists can tell them apart. Unlike invasive breast cancer cells, DCIS cells do not have the capability to spread and grow in distant parts of the body. And unlike invasive breast cancer, DCIS is not life-threatening. Unfortunately, women who are diagnosed with DCIS have a higher than average risk of developing invasive breast cancer later – although some never will. As it stands, there is no proven way to predict which women diagnosed with DCIS will eventually develop invasive breast cancer. But because of the elevated risk, surgery to remove DCIS – generally a lumpectomy with radiation, or mastectomy – has become standard treatment. Treatment options are the same as for early-stage invasive breast cancer. Hwang is exploring to what extent targeted drug treatment with careful follow-up might become a low-risk alternative to surgery for many of these women. The question is hugely important – DCIS is epidemic. Blame mammography. To detect breast cancer at earlier, more treatable stages, mammography guidelines now call for screening women as young as age 40, and compliance with screening guidelines has increased. When there was less screening, many fewer cases of DCIS were diagnosed. Hwang has launched clinical trials to explore drug treatment for DCIS. At an annual retreat for members of the UCSF Helen Diller Family Comprehensive Cancer Center’s Breast Oncology Program, Hwang described some preliminary findings from a study of 62 women diagnosed with DCIS who underwent three months of drug treatment – prior to surgery in most cases. These were DCIS cases in which the abnormal cells possessed estrogen receptors. Estrogen is known to drive the growth of invasive breast cancer that has estrogen receptors. To treat DCIS, Hwang and her UCSF clinical research team used the same estrogen-targeting treatments used to treat women with this so-called estrogen receptor-positive invasive breast cancer. Premenopausal women received three months of tamoxifen treatment, while postmenopausal women were given letrozole for the same duration. Hwang and colleagues imaged DCIS with MRI at baseline and at three months into the study to demonstrate a significant reduction in tumor volume among treated women. In at least one case, there was no remaining DCIS after drug treatment alone. The appearance of cells changed as well. “We found striking differences between tissue at baseline and treated tissue,” Hwang says. Hwang – along with Helen Diller Family Comprehensive Cancer Center researcher Karla Kerlikowske, MD, and colleagues – is also investigating biological markers within DCIS tumors. These markers might prove useful to predict response to therapy, and to predict which types of DCIS might be associated with a greater risk for eventually developing invasive cancer. “There appear to be many interesting targets for therapy in DCIS, in addition to estrogen,” Hwang says. “We would like to look at some of these markers as potential targets.” Hwang now will spearhead a second study, this one focused on postmenopausal women, through the Cancer and Leukemia Group B, a cancer research cooperative group that includes academic medical centers nationwide. Hwang notes that in the past, there has been some resistance to even conducting such studies. Giving drug treatment before surgery is called neoadjuvant therapy. It requires that doctors and patients be willing to delay surgical treatments that have known benefits. However, neoadjuvant therapy already has proved to be safe and effective for some forms of invasive breast cancer; for DCIS, it may help women avoid surgery altogether. Hwang’s research team aims to identify women with DCIS who can safely forgo surgery unless and until their DCIS worsens. She says that she and her colleagues must ultimately show that drug treatment for DCIS can prevent invasive breast cancer from ever arising, and that DCIS can be successfully monitored to determine whether it is progressing toward invasive breast cancer. “I think it’s really important to emphasize that none of this will go forward until physicians and patients are comfortable with the idea that treating DCIS is a way to prevent progression, rather than that DCIS is a disease that needs to be cured,” Hwang says. “This will require a frame shift in how we think of preinvasive cancer of all types, and may have implications for how we intelligently manage the unintended consequences of cancer screening.” Photo by Susan Merrell