PracticeUpdate: Oncology - Winter 2018

EDITOR’S PICKS 13

Circulating Tumor Cell Status Predicts Radiotherapy Benefit in Early Breast Cancer JAMA Oncology

COMMENT By Lee S Schwartzberg MD, FACP I ncreasingly sensitive biomarkers have the potential to stratify patients with early-stage breast cancer (ESBC) into groups that are at higher risk of relapse, raising the possibility of select- ing such patients for more aggressive treatment. Circulating tumor cells (CTCs) have been shown in multiple studies to be prognostic for relapse-free survival in ESBC and are easily obtained via com- mercially available means. The use of this biomarker to determine outcome for locoregional therapies has not pre- viously been reported. Goodman et al assessed two large cohorts, the National Cancer Data Base and a prospective clinical trial called SUCCESS, to determine the influence of positive CTCs on outcome when RT was given or not. In both cohorts, patients who were CTC-positive and received RT had improved survival compared with those who were CTC-positive and did not receive RT. CTC-negative patients had similar outcomes with or without RT. Outcome results in the CTC+/RT+ group were superior whether examined for disease-free survival, locoregion- al-free survival, or overall survival. An intriguing finding in this analysis was theadvantagewithRTappearedconfined only to ESBC patients who underwent breast-conserving surgery. Patients in the CTC+ subgroup who underwent mastec- tomy did not have better outcomes. Do CTCs serve as a surrogate for residual disease in the breast as well as a marker of systemic micrometastasis? Or do CTCs preferentially reside in the breast tissue, making them more susceptible to a course of RT? The biology remains to be elucidated, but this provocative finding should be addressed with a randomized clinical trial. From a clinical perspective, identi- fying a high-risk subgroup for RT within a broader set in whom de-escalation of treatment has been generally shown to be effective (age >65–70; ER+/HER2−) would further personalize breast cancer treatment and target treatment to those who will benefit.

Take-home message • In this cohort study of 1697 patients from a large national database and 1516 patients from a randomized clinical trial with early-stage breast cancer who were evaluated for circulating tumor cell status, patients with at least one circulating tumor cell and who received radiotherapy after breast-conserving surgery had significantly longer local recurrence-free survival, disease-free survival, and overall survival compared with those who did not receive radiotherapy. Patients without circulating tumor cells did not experience longer survival outcomes after radiotherapy. • Circulating tumor cell status might be an important predictive clinical marker for the benefit of radiotherapy in patients with early-stage breast cancer. Abstract

cohort (4-year OS, 94.9% for CTC-positive RT vs 88.0% for CTC-positive non-RT vs 93.9% for CTC-negative RT vs 93.4% for CTC-negative non-RT groups; P< .001) and 5-year DFS within the SUCCESS cohort (88.0% for CTC-positive RT vs 75.2% for CTC-positive non-RT vs 92.3% for CTC-negative RT vs 88.3% for CTC-nega- tive non-RT; P = .04). In the NCDB cohort, RT was associated with longer OS in patients with CTCs (time ratio [TR], 2.04; 95% CI, 1.55-2.67; P< .001), but not in patients without CTCs (TR, 0.80; 95% CI, 0.52-1.25; P= .33). In the SUCCESS cohort, CTC-positive patients treated with RT exhibited longer LRFS (TR, 2.73; 95% CI, 1.62- 4.80; P< .001), DFS (TR, 3.03; 95% CI, 2.22-4.13; P < .001), and OS (TR, 1.83; 95% CI, 1.23-2.72; P = .003). Among patients from both cohorts who underwent breast-conserving surgery, RT was associated with longer OS in patients with CTCs (TR, 4.37; 95% CI, 2.71-7.05; P< .001) but not in patients without CTCs (TR, 0.87; 95% CI, 0.47-1.62; P= .77). Radiotherapy was not associ- ated with OS after mastectomy in CTC-positive or CTC-negative patients. CONCLUSIONS AND RELEVANCE Treatment with RT was associated with longer LRFS, DFS, and OS in patients with early-stage breast can- cer and detectable CTCs. These results are hypothesis generating; a prospective trial eval- uating CTC-based management for RT after breast-conserving surgery in women with ear- ly-stage breast cancer is warranted. Association of Circulating Tumor Cell Status With Benefit of Radiotherapy and Survival in Early-Stage Breast Cancer. JAMA Oncol 2018 May 03;[EPub Ahead of Print], CR Goodman, B-L L Seagle, TWP Friedl, et al. www.practiceupdate.com/c/67675

IMPORTANCE Circulating tumor cells (CTCs) rep- resent the liquid component of solid tumors and are a surrogate marker for residual cancer burden. Although CTC status is prognostic of recurrence and death in breast cancer, its role in guiding clinical management remains unknown. OBJECTIVE To determine whether CTC status is predictive of radiotherapeutic benefit in ear- ly-stage breast cancer. DESIGN, SETTING, AND PARTICIPANTS The cohort studies in the present analysis included patients with stages pT1 to pT2 and pN0 to pN1 breast cancer and known CTC status from the National Cancer Database (NCDB) and the multicenter phase 3 SUCCESS clinical trial. Multivariable parametric accelerated failure time models were used to evaluate the association of CTC status and radiotherapy (RT) with survival out- comes. Data were collected from January 1, 2004, through December 31, 2014, from the NCDB cohort. The SUCCESS trial collected data from September 1, 2005, through September 30, 2013. The analyses were completed from November 1, 2016, through December 17, 2017. EXPOSURE Adjuvant RT. MAIN OUTCOMES AND MEASURES Overall survival (OS), local recurrence-free survival (LRFS), and disease-free survival (DFS). RESULTS A total of 1697 patients from the NCDB (16 men [0.9%] and 1681 women [99.1%]; median age, 63 years; interquartile range, 53-71 years) and 1516 patients from the SUCCESS clinical trial (median age, 52 years; interquartile range, 45-60 years) were identified. Circulating tumor cells were detected in 399 patients (23.5%) in the NCDB cohort and 294 (19.4%) in the SUC- CESS cohort. The association of RT with survival was dependent on CTC status within the NCDB

" From a clinical perspective, identifying a high-risk subgroup for RT within a broader set in whom de-escalation of treatment has been generally shown to be effective (age >65–70; ER+/ HER2−) would further personalize breast cancer treatment and target treatment to those who will benefit. "

VOL. 2 • NO. 3 • 2018