Experts Say DCIS Requires Focus on Genomics and Microenvironment

Meir Rinde
Published: Wednesday, Mar 13, 2019

Norman Wolmark, MD

Norman Wolmark, MD

Identifying patients with ductal carcinoma in situ (DCIS) who are more likely to develop invasive breast cancer remains a challenge, despite decades of research and the development of stratification methods to predict progression and recurrence, experts say. Two major areas of study are the appropriate use of active surveillance and the use of biomarkers observed in the DCIS microenvironment to determine risk.

Most patients with DCIS are treated with surgery, often combined with radiation and hormone therapy. This results in some patients being treated for low-grade precancerous lesions that probably would not develop into invasive cancers.1 At the same time, longterm follow-up of women with minimally treated DCIS showed that invasive cancers and distant metastases are significant concerns, and management of the condition remains controversial.2

Norman Wolmark, MD, chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), laments that DCIS risk is often categorized somewhat arbitrarily. Favorable-risk patients are variously defined by characteristics such as a favorable pattern of microcalcifications, low nuclear grade, estrogen receptor (ER) positivity, and mature age, he said. High-risk patients are said to be ER negative, HER2 positive, of high nuclear grade, and/or younger and to require aggressive treatment.

Wolmark, who discussed DCIS during a presentation at the 36th Annual Miami Breast Conference® (MBCC), Friday, said in his conference abstract that the debate over the treatment of DCIS has been “driven largely by social media, the nonmedical press, and big data mining.” “A conspicuous absence from this perturbing dilemma is data from well-conducted, randomized, prospective clinical trials, “ he said.

Some clarity on grading may eventually be provided by 3 noninferiority trials that are comparing standard therapy with watchful waiting, also known as active surveillance, Wolmark said. Each aims to ultimately include about 900 patients. The oldest is the phase III randomized LORIS trial launched in 2014 by Cancer Research UK.3 Women aged 46 years and older who recently received a diagnosis of DCIS not classified as high grade are assigned to surgery or active monitoring with annual mammograms. Recruitment is scheduled to end in March 2020.

The COMET trial, funded by the Patient- Centered Outcomes Research Institute, opened its first study site in June 2017.4,5 It is enrolling women aged 40 and older with low-risk DCIS and randomizing them to surgery with or without radiation and endocrine therapy or active surveillance with an option for endocrine therapy. The primary outcome measure is new diagnoses of ipsilateral invasive breast cancer after 2 years, with completion planned for 2023. The similar LORD trial, sponsored by the European Organisation for Research and Treatment of Cancer, sets its endpoint further out, to 10 years.6 Accrual began in 2017, and the trial’s estimated completion date is December 2029.

Wolmark, who helped develop the Oncotype DX and Oncotype DX DCIS risk of recurrence assays, said he would have liked to see these data-collection efforts integrate genetic testing, as well. “The major weakness of these 3 trials is that risk is defined based on subjective morphologic interpretations of histologic characteristics and patient age,” he said in his abstract. “The lessons learned from applying genomic algorithms to define risk in invasive breast cancer have not been applied to DCIS. The failure to utilize the DCIS recurrence score [RS] genomic algorithm to define risk is an opportunity lost.”

He also pointed to NSABP B-43, a study comparing breast-conserving surgery, radiation therapy, and 2 infusions of trastuzumab (Herceptin) with breast-conserving surgery and radiation only for HER2-positive DCIS.7 The study, which has recruited more than 2000 patients, will also provide an estimate of risk for HER2-positive disease, he said.

Biology of DCIS

The utility of the Oncotype DX DCIS test to predict the risk of recurrence in women diagnosed with DCIS and treated only with lumpectomy has been repeatedly confirmed.8 Yet Stuart J. Schnitt, MD, chief of Breast Oncologic Pathology at Dana-Farber/ Brigham and Women’s Cancer Center in Boston, Massachusetts, said the test has had much less uptake than the Oncotype DX assay for invasive breast cancer. The DCIS test would be more useful if it also looked at biomarkers in the tissues surrounding the cancer, he said.

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