Increased Risk for Invasive Breast Cancer After DCIS

One of the controversies of routine mammography screening of healthy women is that it detects minimal-risk breast cancer, including the vast majority of ductal carcinoma in situ (DCIS), which has led to concerns of over-diagnosis and over-treatment.

This in turn has led to proposals that DCIS could be managed by active surveillance instead of immediate treatment with surgery.

But a new analysis shows that any diagnosis of DCIS, even when low or intermediate grade, is associated with an increased risk for invasive breast cancer (IBC) and that treatment of DCIS lowers this risk.

The analysis found that risk for IBC after a diagnosis of DCIS was twice that of the general population, and the risk for death caused by breast cancer was 70% higher compared with women without a diagnosis of DCIS.

The study, a retrospective analysis of data from 1988 to 2014, was published online May 27 in the British Medical Journal.

The results also showed that "treatment generally reduces the risk for invasive breast cancer for women with DCIS" and women who received more intensive treatment (such as mastectomy) had lower rates of IBC, the researchers noted.

However, breast cancer experts approached for comment raised several issues with the study and these findings.

"There are many very important serious potential issues with this analysis," said Henry M. Kuerer, MD, professor of breast surgical oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The conclusion that mastectomy for patients — that is, more radical treatment — might lead to improvement is patently false," he told Medscape Medical News.

The management of breast cancer and the quality of mammography has dramatically changed since the period during which the retrospective analysis was conducted, Kuerer pointed out. "Fortunately, we are in a much better era for the management of this disease. Our ability to target and localize small amounts of disease using more sophisticated technology has changed the management of DCIS."

This includes "a much better appreciation" of which patients would "best benefit from adjuvant radiotherapy and endocrine therapy to prevent reoccurrence and/or the development of invasive breast cancer," Kuerer said.

Although national guidelines for tissue processing were in place at the time of the study, the clear margins of resection were not analyzed in detail, he noted. "We know now this is very important," he added.

Active Surveillance for DCIS

One of the proponents for DCIS to be managed by active surveillance rather than immediate surgery is Laura Esserman, MD, MBA, director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco. Pointing out that 95% of DCIS is minimal risk, her group proposed that minimal-risk lesions could be renamed "indolent lesions of epithelial origin" (IDLE) rather than cancer (JAMA. 2009;302:1685-1692), and she argued that active surveillance would "eliminate two thirds of all biopsies."

When approached for comment about the current UK study, Esserman told Medscape Medical News that the findings "do not change my mind at all. In fact this validates my opinion."

"It is incumbent upon us to learn how to better manage DCIS across the spectrum of the types of DCIS. It is likely that some women may be very responsive to risk reduction with endocrine therapy alone and may never need surgery, while others may benefit from a surgical removal," she said.

In the UK study, the increase in risk for occurrence and death took place 10 years and more after diagnosis of DCIS, and the excess risk for death, in spite of all interventions, was 0.6%, Esserman noted. "It is important to use the absolute number rather than the term 'doubling,' which sounds huge," she said.

Also, in the UK study, women with the highest risk for IBC and breast cancer mortality were diagnosed between 1988 and 2000 — the period preceding the use of endocrine therapy in DCIS, she pointed out. "This in fact suggests that the biggest difference can be made with endocrine therapy."

The lack of a significant difference in the rates of IBC and breast cancer mortality in the period right after a diagnosis of DCIS also indicates that local therapy was not reducing risk, Esserman suggested. "This to me suggests that [after a diagnosis of DCIS] women will benefit from overall risk reduction of both breasts, and that endocrine risk reduction is what is likely to make the difference."

Esserman acknowledged that the standard approach to endocrine therapy risk reduction — tamoxifen in young women and aromatase inhibitors in older patients — "can be challenging for women to take. Fortunately, there is emerging evidence that lowering the dose of tamoxifen can vastly reduce the side effects and still retain benefit, and that may be what will make the difference," she said.

Trials to assess this are currently underway, Esserman confirmed. "We will be publishing our long-term active surveillance study soon," she added.

Other Experts Comment

Other experts approached for comment also recommended a careful review of the UK study data both to understand its limitations and to determine the best approaches to reduce the risk for recurrence in patients diagnosed with DCIS. None of the experts, including Esserman, were affiliated with the UK study.

"Clinicians should continue to recommend optimal local treatment to women with DCIS and also discuss the role of endocrine therapy," advised Vered Stearns, MD, who is professor of oncology, breast cancer research chair in oncology, and director of the Women's Malignancies Disease Group at Johns Hopkins University School of Medicine/Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.

"I hope that there will not be a tendency to recommend or choose a mastectomy [after a diagnosis of DCIS]," she told Medscape Medical News.

Stearns noted that women with DCIS who undergo breast-conserving surgery are at a risk for an in-breast recurrence of invasive or noninvasive disease. They are also at higher risk for a new primary breast cancer compared with other women their age who have not had a breast cancer diagnosis.

However, the studies that led to the recommendations for endocrine therapy to reduce the risk for an in-breast recurrence or new primary have consistently demonstrated benefit to women who have received 5 years of tamoxifen or an aromatase inhibitor, Stearns pointed out. And although the individual studies have not demonstrated a survival benefit, this is "likely due to the few events that occur during the observation period," she said.

"Until we have strong biological markers to truly differentiate DCIS or invasive cancer with a high risk of recurrence, invasion, and metastases, I support the use of screening programs in carefully selected patients based on their age, comorbidities, and other characteristics," Stearns said. "Women should continue to have annual screening mammograms as long as they are in good health and have a reasonable life expectancy."

Amanda Mendiola, MD, clinical assistant professor of surgery at the Cleveland Clinic Akron General, Ohio, told Medscape Medical News that the study results "should not guide treatment of low to intermediate grade DCIS." Several prospective trials are looking at optimal treatment in this population, she confirmed, adding that "everyone is anxiously waiting to see what they find."

Until then, the results support current guidelines recommending continued surveillance following a diagnosis of DCIS, Mendiola said. This includes a patient history and physical, and an annual mammogram in women with remaining breast tissue.

Details of the UK Analysis

For their study, Gurdeep S. Mannu, MBBS, DPhil, University of Oxford, UK, and colleagues analyzed data for 35,024 women with a diagnosis of DCIS who participated in the National Health Service breast screening program from its inception in 1988 until December 2014.

The investigators found that 2076 women developed IBC, an incidence rate of 8.82 per 1000 per year, which is more than double that expected from national cancer incidence rates, they comment.

The total of 310 women who died from breast cancer during the study corresponded to a death rate of 1.26 per 1000 women per year — a rate 70% higher than the corresponding national rates for women of the same age in the same calendar year, they note. This increased risk for breast cancer mortality continued for more than two decades.

Although the breast cancer death rate was similar to that expected from national mortality rates in the first 5 years after DCIS diagnosis, it started to climb steadily soon after. In years 5 to 9, the mortality rate from breast cancer increased by a value of 1.98, by a value of 2.99 in years 9 to 14; and by a value of 2.77 after 15 years or more.

Of 29,044 women with unilateral DCIS who underwent surgery, those who received more intensive treatment had lower rates of IBC, the analysis showed. This included women who underwent mastectomy, those who had breast-conserving surgery with radiation, and women with estrogen-receptor positive disease who underwent endocrine therapy. IBC rates were also lower in women with larger final surgical margins.

After 3 years, however, the cumulative rate of IBC increased more steeply for women having breast-conserving surgery, with or without radiotherapy, than those having mastectomy, the analysis showed.

Although there was no overall difference in the adjusted rate of ipsilateral invasive breast cancer based on DCIS grade, this changed significantly over time. Seven or more years after diagnosis, the investigators observed a more rapid increase in the cumulative rate of ipsilateral IBC in women with low/intermediate grade DCIS than in those with high-grade DCIS (P = .01).

"This was due to higher rates of invasive breast cancer in women with low/intermediate grade DCIS who had had breast-conserving surgery rather than mastectomy, whether or not they also had radiotherapy," they explain.

"Although our results suggest that treatment generally reduces the risk of invasive breast cancer for women with DCIS, we acknowledge that some groups of women with favorable characteristics may exist for whom treatment may not be necessary," the authors comment.

"The overall benefits and risks of treatment can be reliably evaluated only in the setting of randomized trials with long-term follow-up," they add, noting that several such trials are currently underway.

The study was funded by Cancer Research UK, NIHR Oxford Biomedical Research Centre, and UK Medical Research Council. Mannu and colleagues reported having no financial conflicts of interest. Esserman disclosed relationships with Quantum Leap Healthcare Collaborative, the Blue Cross/Blue Shield Medical Advisory Panel, and Merck. Stearns reported relationships with AbbVie, Biocept, Pfizer, Novartis, Medimmune, Puma Biotechnology, the data safety monitoring board, and Immunomedics. Mendiola disclosed having no relationships related to the current study. Kuerer disclosed relationships with McGraw-Hill Professional, UpToDate, NEJM Group, and Genentech.

BMJ. Published online on May 27, 2020. Full text

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