Breast cancer is the most common cancer among women in the United States, with an estimated 310,720 cases diagnosed in 2024, according to federal statistics. Within that number exists a wide range of disease types, subtypes, and characteristics, including ductal carcinoma in situ (DCIS), a noninvasive form of the disease.
While DCIS accounts for around a quarter of breast cancer diagnoses in the United States, its prognosis and treatment options are quite different from those of invasive breast cancer. Typically confined to a single milk-producing duct, DCIS is classified as “stage 0” cancer. Experts have long debated whether it should be considered cancer at all or rather some form of hyperplasia that indicates a risk of future cancer.
But considering that around 20% of DCIS cases eventually progress to invasive disease, which can be deadly, experts have historically recommended an aggressive approach to treatment. Current guidelines from the National Comprehensive Cancer Network (NCCN) advise that patients with DCIS receive either a total mastectomy or breast-conserving surgery, potentially followed by radiation and/or antiestrogen therapy. However, such treatments often cause side effects that could potentially be avoided if the DCIS was never going to progress.
So, what is the best approach to DCIS treatment? As suggested by three presenters at the 2024 San Antonio Breast Cancer Symposium (SABCS), held December 10-13, it may be ensuring the patient has as many options as possible—and sufficient data about those options—to make an educated decision with which they feel comfortable.
To Operate or Not to Operate
If DCIS remains localized, it poses little risk to the patient, explained E. Shelley Hwang, MD, MPH, the Mary and Deryl Hart Distinguished Professor of Surgery, vice-chair of research in the Department of Surgery, and a professor of radiology at the Duke University School of Medicine.
“All current treatments for DCIS aim to reduce the risk of future invasive cancer, despite a growing body of evidence that not all DCIS is destined to progress,” Hwang said in a press release. “Thus, current practice may result in the overtreatment of women whose tumors are at low risk of progression, leading to chronic pain, altered body image, reduced quality of life, and other side effects that may be avoidable.”
Unfortunately, researchers don’t have any reliable ways to determine which cases of DCIS will progress and which won’t. Clinical characteristics—such as tumor size, grade, and expression of hormone receptors (HR) and the growth factor receptor HER2—can give some indication of risk, but treatment recommendations do not differ much between risk groups.
In prostate cancer, some patients with low-risk tumors are offered the option of active surveillance, a practice in which patients are not treated immediately but are monitored regularly for signs of disease progression. Researchers have sought to determine whether a similar strategy could be effective in DCIS.
Hwang and colleagues launched COMET, a multicenter, randomized, phase III trial comparing active monitoring to upfront surgery, with or without radiation. They enrolled 995 patients with grade 1 or 2, HR-positive, HER2-negative DCIS with no evidence of invasive cancer and randomly assigned them to either undergo active monitoring or to receive guideline-concordant care consisting of surgery with or without adjuvant radiation. Patients in both treatment arms were allowed to receive endocrine therapy, if desired.
After two years of follow-up, 5.9% of patients in the guideline-concordant care arm and 4.2% of patients in the active monitoring arm had been diagnosed with an invasive recurrence in the same breast. The difference met the threshold for noninferiority, meaning neither treatment was deemed inferior to the other.
The results held true for the 71.3% of patients in the active monitoring arm and 65.5% of patients in the guideline-concordant care arm who received endocrine therapy. Among these patients, the rate of a same-breast invasive recurrence was 7.15% in the guideline-concordant care arm and 3.21% in the active monitoring arm.
“Omission of surgery has been highly controversial, with both patients and providers fearing that it might result in an unacceptably high rate of patients who develop invasive cancer,” Hwang said, noting that their findings—simultaneously published in the journal JAMA—were reassuring. However, another reason active monitoring has been viewed as controversial is the fear that forgoing surgery will cause patients undue anxiety.
“It is critical that we understand how women feel when they are living with an active-monitoring approach and how it impacts their overall quality of life, psychosocial health, worries about DCIS, anxiety and depression, and other related symptoms,” said Ann Partridge, MD, MPH, interim chair of the Department of Medical Oncology at Dana-Farber Cancer Institute and a professor at Harvard Medical School. Partridge and colleagues conducted a secondary analysis of the COMET trial focused on how active monitoring impacted quality of life among patients with DCIS.
Patients enrolled in the trial were asked to complete questionnaires at baseline, six months, one year, and every subsequent year after treatment assignment. The questionnaires surveyed a variety of metrics, including overall physical and mental health-related quality of life, anxiety, depression, worry about DCIS, and treatment-related symptoms.
In both treatment arms, overall health-related quality of life, anxiety, and worry about DCIS remained stable over the two years of follow-up, with no significant difference between the two groups. There was a trend toward higher depression scores and a higher probability of depression over time in the guideline-concordant arm compared with the active monitoring arm.
In terms of physical functioning, patients who received guideline-concordant care reported a significantly greater burden from arm problems, breast pain, and sensory disturbances (such as numbness), on average, although the differences were no longer significant by the two-year mark. Further, when researchers normalized the physical functioning scores by race, age, tumor grade, and use of endocrine therapy, no significant differences were observed.
In a paper published concurrently in the journal JAMA Oncology, Partridge emphasized that the similarity in quality of life observed between the two treatment arms may help empower patients to make the decision that’s right for them. “The data suggest that, in the short term, active monitoring is a reasonable approach in terms of patient experience,” she said in a press release.
What Happens After Surgery?
If patients with low-risk DCIS opt to undergo surgery, they still have several options for continued care. They may receive radiotherapy, endocrine therapy, or both to reduce the risk of their cancer coming back.
For a variety of reasons, some patients may decide against receiving radiation. Researchers have sought to understand whether endocrine therapy may still benefit these patients by helping to prevent recurrence.
Jean L. Wright, MD, chair of the Department of Radiation Oncology at the University of North Carolina and the Lineberger Comprehensive Cancer Center in Chapel Hill, and colleagues combined the data from two clinical trials to evaluate outcomes in patients with good-risk DCIS treated with or without radiotherapy. In this study, the researchers defined good-risk as HR-positive, HER2-negative, grade 1 or 2, 2.5 cm or smaller, and with clear surgical margins of at least 3 mm.
In one of the two trials, NRG/RTOG 9804, patients were randomly assigned to receive radiotherapy or no radiotherapy. In ECOG-ACRIN E5194, patients chose whether to receive radiotherapy or not. In both studies, all patients were permitted to take the endocrine therapy tamoxifen, if desired.
The researchers analyzed results from 878 patients between the two trials, 43% of whom received adjuvant tamoxifen. After a median follow-up of almost 15 years, the risk of a same-breast recurrence was 11.4% for patients treated with tamoxifen and 19% for patients who did not receive tamoxifen, a statistically significant difference. Tamoxifen use was significantly associated with a decreased rate of invasive recurrence but was not associated with a significant difference in the rate of DCIS recurrence.
Because the size of the primary DCIS was significantly associated with the odds of overall recurrence, the researchers adjusted for tumor size and found that tamoxifen was independently associated with a 44% lower risk of overall same-breast recurrence. Similarly, the grade of the primary DCIS was significantly associated with the risk of invasive recurrence. When the researchers adjusted for tumor grade, they found that tamoxifen was independently associated with a 51% lower risk of invasive recurrence.
These data form a poignant follow-up to results presented at last year’s SABCS, in which researchers found that it may be safe for certain patients to skip radiation based on personalized risk factors. Unlike the studies presented this year, last year’s ECOG-ACRIN E4112 trial determined recurrence risk using magnetic resonance imaging (MRI) and a genetic risk score based on the Oncotype DX Breast DCIS Score test.
In the study, patients with low-risk disease were advised to skip radiation, while those with high-risk disease were advised to undergo radiation. Patients who followed recommendations had similar rates of recurrence whether they had low- or high-risk disease.
Overall, these studies represent a clear focus on personalizing treatment strategies for patients with DCIS and giving them robust information with which to make decisions, a direction Wright is passionate about. “The more information we can provide patients about the impact of specific treatments, the more we can empower patients to make choices that are right for them,” she said in a press release. “Tamoxifen, radiation, or both, as well as the omission of any adjuvant therapy, are all reasonable options,” Wright continued. “Now, we have more data to help our patients choose among these.”
