We have been taught that early cancer detection and treatment save lives. The way to cure cancer is to find it early and treat it aggressively. The public has subscribed to this approach in our struggle to “eradicate cancer.” In certain disease types, there is merit to this philosophy. The ability to screen and identify early cases of colorectal cancer, for example, has been extraordinarily impactful. However, in other diseases such as certain breast and prostate cancers, our zeal to find and treat the earliest stages of disease has led to the unfortunate consequences of overdiagnosis and overtreatment.
Kelly Hewitt, MD
Laura J. Esserman, MD, MBA, FASCO
Ductal carcinoma in situ, or DCIS, represents an early and preinvasive stage of the disease. It is often referred to as stage 0 breast cancer, and, in 2023, it is estimated that more than 55,000 women in the United States were diagnosed with this disease.1
Just like other types of breast cancer, not all cases of DCIS are the same. Some DCIS subtypes may never pose a threat, whereas some may represent a risk for developing a slow-growing or hormone-driven invasive breast cancer, and still others may pose a risk for developing HER2-driven or triple-negative breast cancers.
The vast majority of DCIS cases are hormone-driven and are not likely regulated by the immune system. Although we do not know the risk posed by DCIS that is left untreated—mostly because almost all women diagnosed with the disease undergo some type of surgical breast removal—the results from studies are thankfully changing this approach.
Investigating Better Treatment Options for DCIS
It is estimated that between 20% and 40% of DCIS cases will ever progress to invasive breast cancer.2,3 Currently, the standard surgical approach is to treat everyone with DCIS the same way we treat those with stage I disease. Women routinely undergo morbid and life-changing surgery and radiation treatments in an attempt to eradicate the risk for cancer. Approximately one-third of women diagnosed with DCIS undergo mastectomy for disease management, and many also choose contralateral prophylactic mastectomy.4
“What if DCIS is a gateway for prevention and allows us to determine whose DCIS can be made to go away with a course of endocrine treatments that reduce the risk of getting a cancer in either breast?”— KELLY HEWITT, MD, AND LAURA J. ESSERMAN, MD, MBA, FASCO
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The psychological impact of any breast surgery is significant and often not fully appreciated until after irreversible surgical treatment. However, given the slow and likely low rate of disease progression, many women are undergoing what may very well be unnecessary interventions.
It is incumbent upon us to investigate and provide more personalized treatment options for our patients. What if we could identify women at very low risk of disease progression to invasive disease and monitor them over time? What if DCIS is a gateway for prevention and allows us to determine whose DCIS can be made to go away with a course of endocrine treatments that reduce the risk of getting a cancer in either breast? What if we were able to carefully monitor women and use a period of 6 months to determine who is and who is not a good candidate for surgery, as well as who is a good candidate to continue active surveillance and endocrine risk reduction? Why have we made DCIS a surgical emergency when, in fact, it is not?
If many cases of DCIS can be controlled or reversed, with a risk for invasive cancer that is in the same range as women treated with lumpectomy and radiation, why are we treating all cases of DCIS as if they are already stage I or higher cancer? And, on the other side of the coin, how do we identify those with higher-risk disease and treat them appropriately?
Thankfully, the landscape of treatment for DCIS is evolving. The results from several studies suggest that low-risk DCIS represents a substantial fraction of all DCIS cases, and multiple clinical trials have been started to help find better options for DCIS treatment. For example, the COMET trial has recently closed to patient accrual. The trial randomly assigned patients with low- to intermediate-grade hormone receptor–positive DCIS to standard-of-care treatment or active surveillance, with or without the addition of endocrine therapy.5 If we can identify those patients who are at low risk for disease progression, we can, hopefully, save them from unnecessary and aggressive treatments.
Identifying Patients for Active Surveillance
The DCIS: RECAST Trial Ductal Carcinoma in Situ: Reevaluating Conditions for Active Surveillance Suitability as Treatment (ClinicalTrials.gov identifier NCT06075953) was recently approved by the U.S. Food and Drug Administration and will soon begin recruiting patients at multiple institutions nationwide. This study aims to identify which patients are candidates for active surveillance long term with the goal of lowering the risk of ever developing an invasive cancer by treating all patients with hormone receptor–positive DCIS with different hormonal agents and using imaging findings to predict those best suited to avoid surgery.
“Why have we made DCIS a surgical emergency when, in fact, it is not?”— KELLY HEWITT, MD, AND LAURA J. ESSERMAN, MD, MBA, FASCO
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RECAST is comparing several exciting new endocrine risk-reducing strategies that may be as (or more) effective than current standard endocrine risk-reducing approaches and determining whether they are better tolerated. In many ways, RECAST is a prevention trial.
We know that women who are diagnosed with DCIS are likely at an increased risk over their lifetime of developing an invasive breast cancer. Thus, an intervention to reduce that risk, especially one with few side effects, may allow us to prevent the development of any invasive disease, potentially sparing women from unnecessary, irreversible treatment.
Our understanding of the disease is changing, and our standard treatments will hopefully change soon as well.
Refining Treatment for DCIS
It is through ongoing research and clinical trials that we will continue to refine our treatment strategies for this group of women with DCIS. A presurgical window gives us the optimal chance to understand how a particular patient’s disease behaves and how we can best tailor treatment. Although some patients and clinicians are reluctant to “sit on” a diagnosis of DCIS, we have learned from neoadjuvant invasive breast cancer studies, and observations during the COVID-19 pandemic when operations were delayed, that it is safe to treat patients with neoadjuvant endocrine therapy.
In the I-SPY Endocrine Optimization Pilot, we routinely treat women with stage II and III hormone receptor–positive breast cancer with endocrine treatments for 6 months, and these patients have not gone on to have progressive disease. Some clinicians even advocate for the routine use of neoadjuvant endocrine treatment in certain patient populations to learn more about underlying disease, to shrink tumors, and potentially to downstage the axilla.
If we can safely give a patient with invasive breast cancer 6 to 9 months of neoadjuvant endocrine therapy, then we can certainly safely prescribe the treatment for patients with even earlier-stage disease.
Although any change in treatment protocol is scary, and no clinician wants to risk the threat of disease progression in their patients, we must adjust our strategies and evolve with the research findings in the pursuit of overall improved treatment and quality of life for those we seek to help.
Determining Best Candidates for Active Surveillance
The RECAST study is based on the findings of a long-running active surveillance cohort of women with hormone receptor–positive DCIS who opted for neoadjuvant endocrine therapy instead of surgery. The women were followed with close surveillance using serial MRI. Findings from this study showed that baseline MRI scans, and disease changes in the extent of disease and background enhancement from endocrine therapy, may predict patients who are appropriate candidates for active surveillance and endocrine therapy.6
Background parenchymal enhancement on MRI scans is likely an indication of tissue that is activated by hormones and also represents baseline breast cancer risk. Changes in enhancement in areas of DCIS, and other areas of the breast, may allow us to understand who is a candidate for active surveillance with endocrine therapy. Additionally, MRI scans may help to identify patients with underlying invasive disease as well as those who have a focal lesion that has a greater risk for the development of invasive cancer over the subsequent 5 years.
“Our research findings suggest that DCIS is better thought of as a window of opportunity for prevention rather than as a potentially aggressive disease.”— KELLY HEWITT, MD, AND LAURA J. ESSERMAN, MD, MBA, FASCO
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Close monitoring with MRI may help to identify both those patients with a small risk of progression to invasive disease as well as those at higher risk. For example, the RECAST study suggests that semiquantitative MRI features identified those at high risk of progression to invasive disease (in the range of 60%), as well as those whose risk of disease progression is lower (less than 10%), and that these patients can be stratified after 6 months of endocrine therapy.7 The multicenter DCIS: RECAST study is a prospective randomized platform trial designed to validate these findings.
Our research findings suggest that DCIS is better thought of as a window of opportunity for prevention rather than as a potentially aggressive disease. As mentioned previously, the majority of DCIS cases are endocrine-positive, with few to no immune cells. However, there is a small group of women with either hormone receptor–negative or HER2-positive DCIS surrounded by immune cells.
We recently reported exciting data from a phase I study showing that direct injection of an anti–PD-1 inhibitor with Moderna’s triplet mRNA-2752 stimulates T cells and dendritic cells in patients with DCIS, resulting in rapid and robust responses in the setting of immune infiltrates. These results include three patients who achieved a complete response, and avoided surgery and radiation, and remain disease free at least 1 year after in situ vaccination.7
Taking the Word ‘Cancer’ Out of DCIS
Telling a woman she has breast cancer is a life-altering diagnosis. To potentially, albeit unknowingly, use those words to describe DCIS and send her down the path of potentially morbid procedures is life-altering as well. It would likely be helpful to women with DCIS to take the word “cancer” out of the diagnosis, since DCIS, by itself, is not life-threatening.
This approach is true for other cancers, such as Gleason 6 prostate cancer as well. For example, Gleason 6 prostate cancer is a disease that can be surveilled, and we have called for the elimination of the word “cancer” in both diseases.8
We need to rethink what we call cancer and remember our Hippocratic decree to “first, do no harm.” Let’s continue to challenge our understanding of DCIS and evolve to a finer-tuned classification and treatment system for our patients. Now is the time to find a better path forward for all women with DCIS and to start thinking about the diagnosis as a window of opportunity for prevention.
DISCLOSURE: Dr. Hewitt reported no conflicts of interest. Dr. Esserman is the principal investigator of an investigator-initiated trial for the treatment of high-risk DCIS, currently funded by Moderna. She is also an uncompensated board member of Quantum Leap Healthcare Collaborative, a sponsor of the I-SPY trials, including the DCIS: RECAST trial.
REFERENCES
1. American Cancer Society: Key Statistics for Breast Cancer. Available at https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html#:~:text=The%20American%20Cancer%20Society%27s%20estimates,(DCIS)%20will%20be%20diagnosed. Accessed December 11, 2023.
2. Stuart KE, Houssami N, Taylor R, et al: Long-term outcomes of ductal carcinoma in situ of the breast: A systematic review, meta-analysis and meta-regression analysis. BMC Cancer 15:890, 2015.
3. Collins LC, Tamimi RM, Baer HJ, et al: Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: Results from the Nurses’ Health Study. Cancer 103:1778-1784, 2005.
4. van Seijen M, Lips EH, Thompson AM, et al: Ductal carcinoma in situ: To treat or not to treat, that is the question. Br J Cancer 121:285-292, 2019.
5. Hwang ES, Hyslop T, Lynch T, et al: The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: A phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ. BMJ Open 9:e026797, 2019.
6. Glencer AC, Miller PN, Greenwood H, et al: Identifying good candidates for active surveillance of ductal carcinoma in situ: Insights from a large neoadjuvant endocrine therapy cohort. Cancer Res Commun 2:1579-1589, 2022.
7. Esserman L: Intratumoral injection of mRNA-2752 and anti–PD-1 results in rapid regression of HER2-positive and hormone receptor–negative DCIS: Phase 1 study results. AACR Special Conference in Cancer Research: Advances in Breast Cancer Research. Abstract PR07. Presented October 21, 2023.
8. Esserman L, Eggener S: Not everything we call cancer should be called cancer. The New York Times, August 30, 2023. Available at https://www.nytimes.com/2023/08/30/opinion/cancer-breast-prostate-treatment.html. Accessed December 11, 2023.
Dr. Hewitt is Assistant Professor of Surgery in the Division of Surgical Oncology and Endocrine Surgery at Vanderbilt University Medical Center. Dr. Esserman is the Alfred A. de Lorimier Endowed Chair in General Surgery and Director of the University of California San Francisco Breast Care Center.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
