“Ductal carcinoma in situ (DCIS), once a rare entity, now comprises 20% to 30% of newly diagnosed breast cancers detected on mammography and is appreciated to be a widely heterogeneous disease,” said E. Shelley Hwang, MD, MPH, the Mary and Deryl Hart Distinguished Professor at Duke University, who updated attendees on the topic at the 2024 Miami Breast Cancer Conference.1
E. Shelley Hwang, MD, MPH
The spectrum of DCIS ranges from indolent lesions of minimal clinical significance to aggressive lesions with malignant invasive potential. DCIS may, but does not always, progress to invasive cancer. “If and when this will happen is hard to predict,” she said. Clinical and molecular prognostic tools may help delineate subsets of patients for more tailored therapy.
How Much Treatment Is Enough?
Recurrence rates are about 1% per year in low-risk DCIS and about twice that for high-risk or high-grade DCIS—so about 12% over 10 years, rising to 27% in high-risk patients. “Surgery is still the mainstay of therapy for DCIS, and it yields excellent oncologic outcomes,” Dr. Hwang said.
In the United States, almost half of women with DCIS undergo lumpectomy with radiotherapy; about 20% each receive unilateral mastectomy or lumpectomy without radiotherapy; around 8% undergo bilateral mastectomy; and 5% opt for no treatment.2 “None of these treatments appears to make any difference in terms of breast cancer–specific survival…. These patients all have about the same excellent 98% breast cancer–specific survival at 10 years,” she said.
Despite this reassurance, the treatment trend for young women diagnosed with DCIS is a steep rise in bilateral mastectomy, with rates currently around 26% in those up to age 50 and 45% in those up to age 40—rates that are 30% higher than those seen in older patients.3 “Even though this is precancer, this is the kind of treatment that younger women are getting for DCIS in this country,” Dr. Hwang observed.
A 2017 study from Memorial Sloan Kettering Cancer Center can be informative for young patients seeking bilateral mastectomies.4 Among 2,759 patients with DCIS who underwent breast-conserving surgery, the 5- and 10-year cumulative incidence rates of contralateral breast cancer were 3.2% and 6.4%, respectively. “We don’t like to remove a healthy breast, and usually with these numbers, the patient tends to agree with me,” she said.
Sentinel Node Biopsy
It is recommended that patients who opt for a mastectomy for DCIS undergo concurrent sentinel lymph node biopsy. This is supported by a study from The University of Texas MD Anderson Cancer Center, in which a “surprising” 10.7% of 1,234 patients had positive sentinel nodes, including isolated tumors cells in 5.4%, micrometastases in 2.9%, and macrometastases in 2.4%.5 Factors associated with positive findings included the presence of occult invasion (odds ratio [OR] = 3.44; P = .001), diagnosis by excisional biopsy (OR = 1.90; P = .007), DCIS larger than 2 cm (OR = 1.55; P = .030), and multiple interventions performed before sentinel lymph node biopsy (OR = 2.04; P = .022).
Radiotherapy for DCIS
In randomized studies, adjuvant radiotherapy reduces the risk of local recurrence by approximately 50% to 70%, depending on baseline recurrence risk, with benefits seen independent of patient age, tumor size, and margin status.6 For the patient with a baseline recurrence risk of 10%, therefore, a 70% reduction results in a 3% risk.
The RTOG 9804 trial randomly assigned 636 patients with low-risk DCIS to lumpectomy alone or with radiotherapy and found an approximate 1% risk of local recurrence per year without radiation.7 Local recurrence rates at 12 years were 2.8% after radiotherapy and 11.4% with observation alone (about 5% were invasive cancer). Updated results at 14 years found a 15-year cumulative incidence of ipsilateral breast recurrence of 7.1% with radiotherapy and 15.1% with observation (hazard ratio [HR] = 0.36; P = .0007); for invasive locoregional disease, those rates were 5.4% and 9.5%, respectively (HR = 0.44; P = .027). The authors concluded that radiotherapy significantly reduced all and invasive ipsilateral breast cancer recurrences in good-risk DCIS, with durable results.
“Even with low-risk DCIS, there is a continued benefit with radiation, but the benefit is small…. The difference in invasive breast cancer events over time, even out to 15 years, is only about 5%,” Dr. Hwang noted. “Keep in mind the relative and absolute risk of recurrence; in terms of mortality, the impact is minimal.”
DCIS Scoring Systems
Since traditional clinical and pathologic features have failed to identify which patients with DCIS need adjuvant radiotherapy, there is a need for biologic signatures to assess recurrence risk. Prognostic tools have an emerging role in risk stratification and may help to personalize treatment.
The Oncotype DX DCIS scoring system assesses 12 cancer-related genes associated with hormones, HER2, proliferation, invasion, and other factors. Oncotype DX DCIS is expressed in variables from 0 to 100, with a score up to 38 indicating a low risk for recurrence, a score between 39 and 53 indicating intermediate risk, and a score of at least 55 indicating high risk.
In the recently reported ECOG-ACRIN E4112 study, investigators administered adjuvant radiotherapy to patients with negative surgical margins and scores of at lest 39 but not to those with scores less than 39.8 In the overall group, the ipsilateral breast cancer recurrence rate was about 5% at 5 years. Recurrences were observed in 5.5% of women with low DCIS scores (who did not receive radiotherapy) and 4.8% of those with intermediate or high scores (who did receive radiotherapy). “This was a stunning finding,” Dr. Hwang commented. “The biomarker was able to predict which patients can safely avoid radiotherapy.”
The other biomarker in DCIS is detected by the DCISionRT test, which identifies a biologic signature using a panel of seven protein biomarkers (COX-2, FOXA1, HER2, Ki67, p16/INK4A, PgR, and SIAH2) involved in key pathways of the tumor, in combination with four clinicopathologic factors; together, this generates the DCISionRT test result, an individualized Decision Score (DS) that categorizes risk as DS Low (DS ≤ 3) or DS Elevated (DS > 3).
This signature was validated in 526 patients with DCIS treated with breast-conserving surgery with or without radiotherapy, with radiotherapy benefit evaluated by risk group and as a function of DS.9 The DS was prognostic for risk and predicted radiotherapy benefit; it identified a clinically meaningful low-risk group and a group with elevated 10-year risks that received substantial radiotherapy benefit.
A subsequent validation study of 926 women identified three biosignature groups with different outcomes, further refining the risk categories: low risk (DS ≤ 2.8 without radiotherapy), elevated risk (DS > 2.8 without radiotherapy), and residual risk (DS > 2.8 with radiotherapy).10 In patients at low risk, the 10-year recurrence rate was low, and radiotherapy added no benefit. In patients with an elevated risk, radiotherapy reduced recurrences by 75%. In patients with residual risk, radiotherapy reduced recurrences by 79%, though these rates remained high (42% at 10 years).
Endocrine Therapy
In randomized trials, endocrine therapy in patients with DCIS has reduced the risk of recurrence by 30%, independent of age, tumor size, or margin status, though the absolute benefit was dependent on baseline risk. “The big update in this space,” Dr Hwang noted, is a multicenter randomized trial of placebo or low-dose tamoxifen, the Babytam Study.11 At almost 10 years’ follow-up, low-dose tamoxifen reduced ipsilateral breast events by 32% (not statistically significant) and contralateral events by 64% (P = .025). “Babytam is a nice alternative to full-dose tamoxifen,” she commented.
Active Surveillance for Low-Risk DCIS
With such low rates of ipsilateral recurrence, surgery does not alter the natural history of DCIS, so is surveillance a safe option in low-risk patients? Surveillance, Epidemiology, and End Results data show that for patients with grade 1 or 2 tumors, active surveillance was associated with a risk for invasive ipsilateral cancer of 1% to 2% per year.12
Dr. Hwang is now leading the COMET trial, which is randomly assigning women with non–high-grade DCIS to active surveillance or guideline-concordant care.13 Accrual is complete, she said, “and we are excitedly awaiting results,” along with those from multiple other studies (LORIS, LORD, LORETTA) that will help determine the “right-size treatment” for DCIS, she said.
DISCLOSURE: Dr. Hwang has served as a consultant for Exai Bio and Lumicell.
REFERENCES
1. Hwang ES: DCIS updates and future directions. 2024 Miami Breast Cancer Conference. Presented March 9, 2024.
2. Worni M, Akushevich I, Greenup R, et al: Trends in treatment patterns and outcomes for ductal carcinoma in situ. J Natl Cancer Inst 107:djv263, 2015.
3. Byun DJ, Wu SP, Nagar H, et al: Ductal carcinoma in situ in young women: Increasing rates of mastectomy and variability in endocrine therapy use. Ann Surg Oncol 28:6083-6096, 2021.
4. Miller ME, Muhsen S, Olcese C, et al: Contralateral breast cancer risk in women with ductal carcinoma in situ: Is it high enough to justify bilateral mastectomy? Ann Surg Oncol 24:2889-2897, 2017.
5. Francis AM, Haugen CE, Grimes LM, et al: Is sentinel lymph node dissection warranted for patients with a diagnosis of ductal carcinoma in situ? Ann Surg Oncol 22:4270-4279, 2015.
6. Cuzick J, Sestak I, Pinder SE, et al: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12:21-29, 2011.
7. McCormick B, Winter KA, Woodward W, et al: Randomized phase III trial evaluating radiation following surgical excision for good-risk ductal carcinoma in situ: Long-term report from NRG Oncology/RTOG 9804. J Clin Oncol 39:3574-3582, 2021.
8. Khan S, Romanoff J, Gatsonis C et al: Magnetic resonance imaging and a 12-gene expression assay to optimize local therapy for ductal carcinoma in situ: 5-year clinical outcomes of E4112. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-01. Presented December 8, 2023.
9. Bremer T, Whitworth PW, Patel R, et al: A biological signature for breast ductal carcinoma in situ to predict radiotherapy benefit and assess recurrence risk. Clin Cancer Res 24:5895-5901, 2018.
10. Vicini FA, Mann GB, Shah C, et al: A novel biosignature identifies patients with DCIS with high risk of local recurrence after breast conserving surgery and radiation therapy. Int J Radiat Oncol Biol Phys 115:93-102, 2023.
11. De Censi A, Lazzeroni M, Puntoni M, et al: 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer. Abstract GS4-08. Cancer Res 83(suppl 5):GS4-08, 2023.
12. Ryser MD, Weaver DL, Zhao F, et al: Cancer outcomes in DCIS patients without locoregional treatment. J Natl Cancer Inst 111:952-960, 2019.
13. 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 (DCIS). BMJ Open 9:e026797, 2019.
