Varied Reactions to Study Finding That Preventing Ipsilateral Recurrence Did Not Prevent Death From Breast Cancer


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Steven A. Narod, MD

Otis W. Brawley, MD

Laura Esserman, MD, MBA

The ductal carcinoma in situ is the cancer, and the recurrence is the recurrence. Just like invasive cancer. And if you prevent that invasive cancer recurrence, it doesn’t prevent death.

—Steven A. Narod, MD

Women diagnosed with ductal carcinoma in situ have a low risk of dying of breast cancer, according to an observational study looking at data from 108,196 women diagnosed with ductal carcinoma in situ between 1988 and 2011.1 The breast cancer–specific mortality rate for these women was 1.1% at 10 years and 3.3% at 20 years. Mortality rates were higher for black women and women diagnosed before the age of 35. “The risk of death increases after a diagnosis of ipsilateral second primary invasive breast cancer, but prevention of these recurrences by radiotherapy does not diminish breast cancer mortality at 10 years,” the authors concluded in JAMA Oncology.1

This study garnered national media coverage, including The New York Times, The Washington Post, USA Today, TIME magazine, National Public Radio, and the PBS NewsHour. That coverage included varied reactions to the study and its implications for the treatment of women diagnosed with ductal carcinoma in situ.

“The finding of greatest clinical importance was that prevention of ipsilateral invasive recurrence did not prevent death from breast cancer,” the authors stated in their report and lead author Steven A. Narod, MD, confirmed in an interview with The ASCO Post. Dr. Narod is Senior Scientist and Director of the Familial Breast Cancer Research Unit at Women’s College Research Institute, Toronto, Ontario, Canada. The investigators also found that after adjusting for tumor size, grade, and other factors, “the difference in survival for mastectomy vs lumpectomy was not significant.”

Practice-Changing or Not?

The authors of the study did not deem their finding practice-changing. Some news reports, however, suggest the finding that breast cancer–specific mortality for women diagnosed with ductal carcinoma in situ was similar no matter what the treatment—and just 1.8 times higher than for women in the general population—indicating it does not need to be treated. The New York Times headlined its article on the study “Early-Stage Breast Condition May Not Require Treatment”2 and listed the following as one of the “provocative questions” raised by the study: “Is there any reason for most patients with the diagnosis to receive brutal therapies?”

“Let me emphatically say that I do not understand how an observational study of patients for whom we don’t have complete characterization of their ductal carcinoma in situ, who were treated in different ways, and who were not randomly assigned could possibly be a practice-changing study,” stated Monica Morrow, MD, Chief, Breast Service, Memorial Sloan Kettering Cancer Center, New York, in an interview with The ASCO Post. “That is not how we change practice.”

Dr. Morrow added that she considers calls for additional trials to be appropriate. “But telling people they should change practice on the basis of this is a mistake. I think the most important message of this study is that when you treat ductal carcinoma in situ, the risk of breast cancer deaths is incredibly low. What we don’t know is whether or not the risk of breast cancer deaths will be equally low if we don’t treat ductal carcinoma in situ. That is a giant extrapolation of the data, saying the outcome of data is good and therefore we don’t have to treat. Those are not the same things. But that is what some people are saying.”

Commenting on the study for the PBS NewsHour, Dr. Morrow said that she thinks what the study “does tell us is that, to date, physicians have been pretty good at selecting low-risk ductal carcinoma in situ, which can be treated minimally with lumpectomy alone. I think it says we should think hard about expanding the indications for minimal treatment. But I think it’s also important for women to be aware that we can only say there is nothing there but ductal carcinoma in situ after we have removed the entire area. Twenty percent of women who are diagnosed as having ductal carcinoma in situ on a needle biopsy will actually be found to have invasive cancer when you remove the entire area.”3

Study Details

Information about study patients’ age at diagnosis, race/ethnicity, pathologic features, date of second primary breast cancer, cause of death, and survival data was abstracted from the most recent Surveillance, Epidemiology, and End Results (SEER) 18 registries database. According to the study authors, “the SEER18 database covers approximately 28% of the U.S. population (based on the 2010 census).” The mean age of the patients at diagnosis was 53.8 (range, 15–69) years, and the mean duration of follow-up was 7.5 (range, 0–23.9) years.

At 20 years, the overall breast cancer–specific mortality for women diagnosed with ductal carcinoma in situ was 3.3% (95% confidence interval [CI], 3.0%–3.6%) but higher for women diagnosed before age 35, 7.8% vs 3.2% for older women (hazard ratio [HR] = 2.58 [95% CI, 1.85–3.60]; P < .001), and for blacks, 7.0% vs 3.0% for non-Hispanic whites (HR = 2.55 [95% CI, 2.17–3.01]; P < .001). The risk of dying of breast cancer was higher among women who experienced an ipsilateral invasive breast cancer (HR = 18.1 [95% CI, 14.0–23.6]; P < .001).

The use of radiotherapy with lumpectomy reduced the risk of developing an ipsilateral invasive recurrence from 4.9% to 2.5% for lumpectomy alone “but did not reduce breast cancer–specific mortality at 10 years (0.9% vs 0.8%),” the authors noted. After adjusting for tumor size, grade, and other factors, the difference in survival was not significant for patients who underwent mastectomy vs lumpectomy (HR = 1.20 [95% CI, 0.96–1.50]; P = .11).

Risk Factors for Mortality

Only 1.2% of women in the study were diagnosed with ductal carcinoma in situ before age 35, “but for them, mortality was approximately 17 times greater than expected in the 9 years following diagnosis,” the authors reported. Dr. Narod explained that this is the relative risk compared with the baseline risk for the general population. “Very few 35 year olds die of breast cancer,” he said, so even 17 times that number is “is not very big. If the same risk was seen in a 50-year-old woman, it would be much different than in a 35-year-old woman.”

Dr. Morrow noted that older women who have screening mammographies often present with microscopic areas of calcium deposits, but that “is not what these young women present with. They present with lumps or nipple discharge, and the bigger the area of the ductal carcinoma in situ, the bigger the chance of sampling error with core needle biopsy as well as in the surgical specimen. The greater the possibility that there may be undiagnosed cancer, number 1. And number 2, we know from clinical trials that have been done in the past that young women who are treated with lumpectomy alone without radiation tend to have a higher rate of local recurrence.”

The breast cancer–specific mortality rate was also higher for black women than non-Hispanic white women. “The proportion of black and white women treated with mastectomy and radiotherapy was similar,” the authors wrote. “It is improbable that black women had inferior survival because of less-frequent screening or inadequate treatment.”

“Other important risk factors for mortality following ductal carcinoma in situ included estrogen receptor status, high grade, tumor size, and comedonecrosis,” the researchers reported. “In the first 10 years after diagnosis, the mortality rate for women with estrogen receptor–negative cancers exceeded that for estrogen receptor–positive cancers, but at 20 years, the mortality rates had reversed. Among the deaths from estrogen receptor–negative ductal carcinoma in situ, 13.4% occurred in years 10 to 19. In contrast, among the deaths of patients with estrogen receptor–positive ductal carcinoma in situ, 26.8% occurred in years 10 to 19.”

Clinical Course Similarities

“It is well known that estrogen receptor–negative cancers do badly but only transiently,” Dr. Narod noted. “The estrogen receptor–positive ones tend to lie dormant, and then they can wake up to kill you after 15 years.” This relationship between estrogen receptor status and mortality risk “is one of several similarities between the clinical course of women with ductal carcinoma in situ and that of women with small invasive cancers,” the investigators reported.

“That is really important,” Dr. Narod stated. “Ductal carcinoma in situ resembles cancer in almost every way. The estrogen receptor pattern is the same, the age pattern is the same, the black women pattern is the same, and most important, preventing recurrence does not prevent death. It has been known for years, since NSABP trials compared lumpectomy and mastectomy, that preventing breast cancer recurrence didn’t prevent death from invasive cancer. Now we show exactly the same thing for ductal carcinoma in situ, and people don’t get it. They still think that ductal carcinoma in situ is the precursor, and the recurrence is the cancer. No: The ductal carcinoma in situ is the cancer, and the recurrence is the recurrence. Just like invasive cancer. And if you prevent that invasive cancer recurrence, it doesn’t prevent death,” Dr. Narod asserted.

In-Breast Recurrence

Among the 3% of women in the study who died of breast cancer, 54% of them did not experience an in-breast recurrence (ipsilateral or contralateral). “That leads me to think that when ductal carcinoma in situ was removed by the surgeon, it had already spread around the breast, and it took years, up to 20 years, for those cells that had spread to flourish and to be metastatic and to ultimately cause the breast cancer death,” Dr. Narod said on the PBS NewsHour.3

The other 46% will “experience an in-breast ipsilateral recurrence or contralateral breast cancer,” Dr. Narod told The ASCO Post. “It’s not to say that that killed them.”

The risk of contralateral invasive recurrence was higher than the risk of ipsilateral invasive recurrence, 6.2% vs 5.9%, at 20 years for all women in the study. “The ipsilateral [recurrence rate] was reduced by radiotherapy. Had there been no radiotherapy, the ipsilateral [recurrence rate] would have been higher than the contralateral [recurrence rate],” Dr. Narod explained. “But certainly, ductal carcinoma in situ predisposes to contralateral. We need to explore why that it is. Contralateral breast cancer is increased about twice as much as we would expect in an average woman,” he added.

“The risk of contralateral breast cancer following ductal carcinoma in situ is identical to the risk of contralateral breast cancer following stage I breast cancer. So it is another reason to say that ductal carcinoma in situ is an early form of breast cancer, not precancer,” Dr. Narod said. He and his coauthors acknowledged, “although it is accepted that, for women with invasive breast cancer, prevention of in-breast recurrence does not prevent death for women with small invasive breast cancers, this has not been widely accepted for women with ductal carcinoma in situ.” Dr. Narod told The ASCO Post that although he had thought the publication of the study would increase that acceptance, “it turns out not to be the case” or at least “not as much as I had hoped.”

Monitoring vs Surgery

Dr. Morrow noted that an ongoing trial, the LORIS (low-risk) ductal carcinoma in situ study, is comparing active monitoring with surgery for women with non–high-grade ductal carcinoma in situ. According to trial information posted online by the trial sponsor, the University of Birmingham, the target patient population is women aged ≥ 46 years with histologically confirmed non–high-grade ductal carcinoma in situ. The anticipated recruitment end date is 2020.4,5

The primary outcome measure is ipsilateral invasive breast cancer–free survival time, but investigators are also looking at psychological issues related to active monitoring or surgery. “Although some treating cancer doctors, particularly many epidemiologists, are going on about overtreatment of ductal carcinoma in situ,” Dr. Morrow said, “research that we have done shows that the driving force behind mastectomies in ductal carcinoma in situ is not surgeons; it’s patient desire.”

That research involves work with a group called CANSORT at the University of Michigan, which studies decision-making and breast cancer. Dr. Morrow explained: “In one of our first studies, we asked women with ductal carcinoma in situ and early-stage breast cancer, ‘Who made the decision about what surgery you should have: you, your doctor, or you and your doctor as a shared decision?’ If the doctor made the decision, the mastectomy rate was 5%. If the decision was shared, it went up to about 16%, and if the patient made the decision, the mastectomy rate went up to about 28%.”

Dr. Morrow concluded: “So it is a patient-driven decision, even though most patients will tell you that they have been told that there is no difference in breast cancer survival between lumpectomy and radiation and mastectomy. Patients opt for more treatment.”

Call for Additional Studies

The study authors noted that “potential treatments that affect mortality are deserving of study,” and other individuals have cited the need for additional ductal carcinoma in situ trials. The article in The New York Times reported that Otis W. Brawley, MD, Chief Medical Officer of the American Cancer Society, said that before changing treatment approaches to ductal carcinoma in situ, a large clinical trial is needed to define which patients would most benefit from treatment for ductal carcinoma in situ and which might forgo active treatment or might be candidates for risk-reducing endocrine therapy.2

In an editorial accompanying the study in JAMA Oncology,6 Laura
Esserman, MD, MBA
, and Christina Yau, PhD, of the University of California, San Francisco, stated: “The analysis of Narod et al fuels a growing concern that we should rethink our strategy for the detection and the treatment of ductal carcinoma in situ.”

Ductal carcinoma in situ “may best represent an opportunity to alter the environment of the breast. For the lowest-risk lesions, observation and prevention interventions alone should be tested either in trials or as part of a registry . Diet, exercise, moderate alcohol intake, and avoidance of postmenopausal hormone therapy with progesterone-containing regimens should be the starting point for prevention,” the editorial continued.

“For premenopausal women, tamoxifen therapy is a good choice for hormone-positive low-grade, low-risk ductal  carcinoma in situ. For postmenopausal women, aromatase inhibitor therapy has been shown to have a bigger impact on risk reduction. Raloxifene hydrochloride [Evista] is a better-tolerated prevention alternative,” continued Drs. Esserman and Yau. “Adverse effects of endocrine risk-reducing agents can be a problem. Different doses and schedules should be investigated to mitigate adverse effects, improve tolerability, and avoid serious complications.”

Drs. Esserman and Dr. Yau concluded that they are initiating studies to determine whether they can activate the immune system to reverse high-risk ductal carcinoma in situ “with a more targeted approach to address the specific mortality risk.” ■

Disclosure: Drs. Narod and Morrow reported no potential conflicts of interest.

References

1. Narod SA, Iqbal J, Giannakeas V, et al: Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. August 20, 2015 (early release online).

2. Kolata G: Early-stage breast condition may not require cancer treatment. The New York Times, August 20, 2015.

3. Study raises questions about treatment for early breast cancer. PBS NewsHour, August 20, 2015.

4. Sussex Health Outcomes Research & Education in Cancer (SHORE-C): A phase III trial of surgery versus active monitoring for LOw RISk DCIS (LORIS). Available at http://shore-c/sussex.ac.uk/loris.htm. Accessed September 8, 2015.

5. LORIS: A phase III trial of surgery versus active monitoring for low risk ductal carcinoma in situ (DCIS). Available at http://www.birmingham.ac.uk/loris. Accessed September 8, 2015.

6. Esserman L, Yau C: Rethinking the standard for ductal carcinoma in situ treatment. JAMA Oncol. August 20, 2015 (early release online).

 


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