Navigating Treatment Options for Patients With Early-Stage Breast Cancer

Aditya Bardia, MD, MPH

Genetic advances have helped elucidate the heterogenous nature of breast cancer, however optimal strategies for patients with early-stage disease still need to be ironed out. Surgery, systemic therapy, and radiation therapy are 3 therapeutic approaches to consider for patients with early-stage breast cancer according to current guideline recommendations.¹ As more information about how breast cancer subtypes respond to treatment come to light, the clinical management of patients with early-stage disease is rapidly evolving.

Recent improvements in imaging, pathologic review, surgical techniques, and radiation design, combined with new information regarding tumor biology, has led to a more personalized approach for patients with ductal carcinoma in situ² (DCIS: Figure 1). Investigators are examining watch-and-wait approaches as well as the use of neoadjuvant therapies prior to statandard of care surgery for patients with low-risk disease. Additionally, the use of pathological complete response (pCR) as a clinical end point has expanded access to treatment options for patients who may otherwise not benefit from delayed treatment.

Waves of Change for Patients With DCIS

It is estimated that 20% to 30% of DCIS will progress to invasive cancer. The long-term survival rate for patients with breast cancer treated for DCIS exceeds 95%.³ Treatment for DCIS has historically been based on studies of invasive breast cancer and includes a combination of surgery, radiation and hormonal therapy. However, deducing treatment strategies from these types of studies has been decried more recently by experts as overtreatment. This overdiagnosis and treatment based on mammographic screening are leading investigators to lean on strategies that employ a watch-and-wait approach.

“The 2 broad approaches for DCIS are (1) consideration of lumpectomy, and (2) mastectomy—especially if there is multicentric DCIS, meaning DCIS is in multiple parts of the breast,” said Aditya Bardia, MD, MPH, in an interview with OncLive^®.

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For an individual lesion, DCIS breast-conserving therapy is an option, but if there are multiple DCIS lesions, doing multiple lumpectomies can be difficult. That’s where one could consider mastectomy,” said Bardia, an attending physician at Massachusetts General Hospital Cancer Center and an assistant professor of medicine at Harvard Medical School. “But you have to discuss these options with patient; mastectomy has its own psychological and physical consequences. Surgery can have complications as well. You have to carefully weigh risks and benefits.”

Overtreatment and uncertainty in standards of care

Controversy regarding DCIS overtreatment stems from demonstrated lack of mortality benefit, he explained. In an observational study, investigators analyzed breast cancer-specific mortality in a cohort of 108,196 women with DCIS. Among patients who received lumpectomy, radiotherapy was associated with a reduction in the risk of ipsilateral invasive recurrence at 10 years (2.5% vs 4.9%; adjusted HR, 0.47; 95% CI, 0.42-0.53; P < .001) but not of breast cancer—specific mortality at 10 years (0.8% vs 0.9%; HR, 0.86; 95% CI, 0.67-1.10; P = .22). Further, the 20-year breast cancerspecific mortality rate was 3.3%.⁴

Patients who developed an ipsilateral invasive recurrence were 18.1 times more likely to die of breast cancer than women who did not. For patients who had a lumpectomy, the use of radiotherapy reduced the risk of developing an ipsilateral invasive recurrence from 4.9% to 2.5% but did not reduce breast cancer—specific mortality at 10 years (0.9% vs 0.8%). Similarly, patients who underwent unilateral mastectomy had a lower risk of ipsilateral invasive recurrence at 10 years than patients who underwent lumpectomy (1.3% vs 3.3%) but had a higher breast cancer–specific mortality (1.3% vs 0.8%). Patients who had a mastectomy had cancers with a larger mean size and higher grade than patients who had a lumpectomy.⁴

“The question is, [when] you’re treating something, [you judge whether] is it important from the perspective that it will impair either survival or quality of life. That has been the conundrum with DCIS—that if someone has a mastectomy, [you wonder if there] was overtreatment. Maybe DCIS wouldn’t [have caused] problems for the rest of the life of the individual.

“The other scenario, [however,] is where somebody with DCIS will have the disease progress to invasive breast cancer, with even… [progression to] metastatic disease. [Clearly, that] could potentially impair quality of life and survival for the individual, and thus treating DCIS [more aggressively] makes sense in this scenario,” he said.

Currently, almost 70% of women with unilateral DCIS undergo breast conserving surgery, 20% undergo unilateral mastectomy, and about 10% elect for bilateral mastectomy.

Neoadjuvant endocrine therapy

To decrease the risk of ipsilateral breast tumor recurrence following surgery, the NCCN guidelines recommend endocrine therapy, noting that the benefit of therapy for patients with estrogen receptor—negative disease is uncertain. Several studies are investigating the use of neoadjuvant endocrine therapy for DCIS as potential alternative to surgery.

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Median reductions from baseline MRI volume (1.4 cm³) were 0.6 cm³ (61.0%) at 3 months (P < .001) and 0.8 cm³ (71.7%) at 6 months (P < .001). Per study protocol patients underwent surgery following 6 months of treatment. Of the 59 patients, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in 6 patients (10%), and no residual DCIS or invasive cancer was seen in 9 patients (15%). Investigators concluded that the findings support extended endocrine therapy as a nonoperative treatment option for some patients with DCIS.

Active Surveillance

With increased detection of DCIS, gene expression profiles are more commonly being used to identify patients who might be candidates for treatment deescalation.³ Risk stratification tools such as the Oncotype DX may aid in identifying patients who would benefit from more aggressive treatment. The 21-gene assay provides results as a risk score that can be used to refine treatment strategies for patients who are at low, intermediate, or high risk of recurrence or invasive disease in the subset of patients with DCIS.¹

For patients with low-risk DCIS, techniques for minimizing radiation exposure following breast conserving surgery are under way. Although radiation therapy is usually prudent as a component of breast conserving surgery in DCIS, selected low-risk patients may do best with the omission of surgery and adjuvant radiation therapy based on trial data.

The Comparison of Operative to Monitoring and Endocrine Therapy study, or COMET (NCT02926911), is a randomized study looking at guideline concordant care versus active surveillance.6 Investigators plan to enroll a total of 1200 patients with the primary outcome of evaluating the ipsilateral invasive breast cancer rate. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes.

Patients in the guideline concordant care arm will undergo surgery as well as radiotherapy when appropriate. Patients in the active surveillance group will be monitored closely with surgery only on identification of invasive breast cancer. Endocrine therapy will be an available option to patients in both groups.

“While a bit controversial, clinical trials such as COMET are evaluating watchful waiting for low-risk DCIS. It is important to thoughtfully discuss treatment with patients and understand their preferences before finalizing treatment,” Bardia stated.

Using Prognostic Markers to Guide Treatment Decisions

Ki67

Work still needs to be done to identify better markers to understand the link between tumor response, relapse risk, and diseasefree survival (DFS) and overall survival (OS). Samples collected from patients treated with neoadjuvant therapy are providing insights to the molecular basis to conclude more precise approaches to systemic treatments of breast cancer.

The use of Ki67 staining in patients with ER-positive breast cancer demonstrated efficacy as a marker for predictive of improved rates of breast conservation, the identification of extreme responders on the basis of preoperative endocrine prognostic index (PEPI) and provided rational to avoid chemotherapy on the basis of highly favorable prognosis in some patients.⁷

Ki67 was utilized in the phase II neoMONARCH trial, which examined neoadjuvant therapy with the CDK4/6 inhibitor abemaciclib (Verzenio) plus anastrozole in patients with HR-positive/HER2-negative early-stage breast cancer. Results showed that the combination induced complete cell cycle arrest, which was the study’s primary end point, as measured by Ki67 for 67.8% of patients. For those treated with abemaciclib alone, cell cycle arrest was achieved for 57.7% of patients; for those who received anastrozole alone, 14.3% of patients experienced cell cycle arrest.⁸

“In the HR-positive setting, a surrogate biomarker called [residual cancer burden] which is the change Ki67 [levels] from day 1 to 15, can provide surrogacy regarding long-term outcomes with NET [neoadjuvant endocrine therapy]. So, one could look at change in Ki67 as a biomarker end point to evaluate efficacy of NET in patients with HR-positive breast cancer,” Bardia said.

pCR

Several neoadjuvant trials have indicated that pCR correlates with long-term outcomes and is a proxy for DFS and OS. Highly proliferating carcinomas such as TNBC or HER2-positive tumors more commonly attain pCR readings than do luminal tumors.⁹ The term pCR refers to the lack of residual invasive cancer on histologic evaluation of the resected breast primary and regional lymph nodes following neoadjuvant therapy. For patients with early-stage breast cancer who are considered high-risk for distant disease recurrence and risk of death, the use of pCR an measure of clinical efficacy may predict clinical benefit within several months of treatment, addressing unmet treatment needs in a shorter timeframe compared to conventional therapies.¹⁰

“The presence of pCR after neoadjuvant chemotherapy is associated with better outcomes as compared with patients who do not have a pCR. So, it is a robust prognostic biomarker,” said Bardia said.

In 2014, the FDA listed pCR as an acceptable surrogate end point of clinical benefit in neoadjuvant clinical trials in which agents were undergoing accelerated drug approval.¹⁰

However, for HR-positive disease treated with neoadjuvant chemotherapy or endocrine therapy, high pCR rates are infrequent; therefore, other biomarker end points have been suggested, such as residual cancer burden, tumor size, and nodal status to provide a surrogate estimate of disease recurrence risk.

References

1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Breast Cancer (version 2.2020). nccn.org/ professionals/physician_gls/pdf/breast.pdf. Accessed February 20, 2020.
2. Doke K, Butler S, Mitchell MP. Current therapeutic approaches to DCIS. J Mammary Gland Biol Neoplasia. 2018;23(4):279-291. doi: 10.1007/s10911-018-9415-1.
3. Hwang ES, Malek V. Estimating the magnitude of clinical benefit of local therapy in patients with DCIS. Breast. 2019;48(suppl 1):S34- S38. doi: 10.1016/S0960-9776(19)31120-8.
4. Narod SA, Iqbal J, Giannakeas V, Sopik V, Sun P. Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. 2015;1(7):888-896. doi: 10.1001/jamaoncol.2015.2510.
5. Hwang ES, Hyslop T, Hendrix LH, et al. Phase II single-arm study of preoperative letrozole for estrogen receptor—positive postmenopausal ductal carcinoma in situ: CALGB 40903 (Alliance) [published online ahead of print March 3, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.00510.
6. Hwang ES, Hyslop T, Lynch T, et al. The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomized controlled clinical trial for low-risk ductal carcinoma in situ (DCIS). BJM Open. 2019;12:9(3):e026797. doi: 10.1136/ bmjopen-2018-026797.
7. Reinert T, Gonçalves R, Ellis MJ. Current status of neoadjuvant endocrine therapy in early stage breast cancer. Curr Treat Options Oncol. 2018;19(5):23. doi: 10.1007/s11864-018-0538-9.
8. Martin M, Hurvitz SA, Chan D, et al. Final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract PD5-01.
9. Chaudhary LN, Wilkinson KH, Kong A. Triple-negative breast cancer: who should receive neoadjuvant chemotherapy? Surg Oncol Clin N Am. 2018;27(1):141-153. doi: 10.1016/j.soc.2017.08.004.
10. Table of surrogate endpoints that were the basis of drug approval or licensure. FDA website. www.fda.gov/drugs/developmentresources/ table-surrogate-endpoints-were-basis-drug-approval-orlicensureUpdated September 30, 2019. Accessed February 20, 2020.

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In a phase II single-arm study, postmenopausal patients with estrogen receptor (ER)-positive DCIS were treated with aromatase inhibitor letrozole (Femara) 2.5 mg/day for 6 months prior to surgery. Breast MRIs were conducted at baseline, 3 months, and 6 months with a primary end point of change in MRI volume of disease. Of 79 patients enrolled, 67 had data available at analysis. Significant imaging and biomarker changes were observed.⁵

The National Comprehensive Cancer Network (NCCN) guideline for patients who receive a diagnosis of DCIS following mammography recommend lumpectomy without lymph node surgery with or without radiation therapy (whole breast or accelerated partial breast); or total mastectomy with or without sentinel node biopsy and optional reconstruction (Figure 2).¹