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Breast conservation surgery and mastectomy have similar locoregional recurrence following neoadjuvant chemotherapy: results from over 1400 patients on the prospective, randomized I-SPY2 Trial
Rita Mukhtar^*1, Harrison Chau³, Hannah Woriax⁴, Mara Piltin², Gretchen Ahrendt⁵, Julia Tchou⁶, Hongmei Yu⁷, Qian Ding⁷, Catherine L. Dugan¹, Jori Sheade⁸, Angelena Crown²¹, Michael Carr⁹, Jasmine Wong¹, Jennifer Son¹⁰, Rachel Yang¹, Theresa Chan¹¹, Alicia Terando¹², Michael Alvarado¹, Cheryl Ewing¹, Jennifer Tonneson¹³, Nina Tamirisa¹⁴, Rebekah Gould¹⁴, Puneet Singh¹⁴, Constantine Godellas¹⁵, Kelsey Larson¹⁶, Akiko Chiba⁴, Roshni Rao¹⁷, Kathy Czaplicki¹⁸, Lauren Postlewait¹⁹, Marie C. Lee²⁰, William F. Symmans¹⁴, Laura Esserman¹, ISPY-2 Locoregional Working Group¹, Judy Boughey^2
1University of California San Francisco, San Francisco, CA; ²Mayo Clinic, Rochester, MN; ³University of California San Diego, San Diego, CA; ⁴Duke University Medical Center, Durham, NC; ⁵University of Colorado, Aurora, CO; ⁶University of Pennsylvania, Philadelphia, PA; ⁷Quantum Leap Healthcare, San Francisco, CA; ⁸Northwestern Medicine, Chicago, IL, IL; ⁹University of Louisville, Louisville, KY; ¹⁰Georgetown University, Washington, ; ¹¹Ironwood Cancer and Research Centers, Phoenix, AZ; ¹²Cedars-Sinai Cancer at Huntington Hospital Cancer Center, Pasadena, CA; ¹³Oregon Health and Science University, Portland, OR; ¹⁴University of Texas MD Anderson Cancer Center, Houston, TX; ¹⁵Ascension Medical Group, Elk Grove Village, IL; ¹⁶University of Kansas, Kansas City, KS; ¹⁷Columbia University, New York, NY; ¹⁸Loyola University Medical Center, Maywood, IL; ¹⁹Emory University, Atlanta, GA; ²⁰Moffitt Cancer Center, Tampa, FL; ²¹Swedish Cancer Institute, Seattle, WA

Background:
Neoadjuvant chemotherapy (NAC) increases rates of successful breast conserving surgery (BCS) in patients with breast cancer who would otherwise require mastectomy based on disease extent at diagnosis. However, some studies have suggested that BCS after tumor down-staging with NAC may be associated with increased risk of locoregional recurrence (LRR), with conflicting results in the literature. The aim of this study was to assess LRR rates following NAC and determine if type of surgery impacts LRR.

Methods:
We analyzed outcomes of all patients enrolled on the I-SPY2 trial, an adaptive, multicenter trial enrolling patients with clinical stage II-III, molecularly high-risk primary breast cancer treated with NAC followed by surgery from 2010-2021. We evaluated the impact of type of surgery (BCS vs mastectomy) on time to locoregional recurrence (LRR). Cox proportional hazards models were used to evaluate the associations between surgical procedure, patient age, tumor receptor subtype, clinical stage, and Residual Cancer Burden (RCB) with time to LRR. RCB was bimodally categorized as classes 0 and 1 (pathologic complete response, pCR, or minimal residual invasive disease), or classes 2 and 3 (significant residual invasive disease).

Results:
Of 1,478 patients, 644 (43.6%) underwent BCS and 834 (56.4%) underwent mastectomy. Overall pCR was 35.9% and varied between the two groups (41.7% in those with BCS and 31.5% in those with mastectomy) Those undergoing mastectomy were more often <50 years of age (62.0% vs 49.9%, p<0.0001), clinical stage III (72.0% vs 28.0%, p<0.0001), and more likely to have RCB class 2/3 disease on final pathology (63.0% vs 37.0%, p<0.0001). Median follow up time was 3.5 years (range 0.4-10.2). In total 91 patients (6.2%) experienced a LRR event. In univariate and multivariate analyses, the surgical procedure performed was not associated with LRR. The unadjusted incidence of LRR was 5.4% in those undergoing BCS, and 6.7% in those undergoing mastectomy (p=0.28, log rank). The strongest predictor of LRR was RCB class (adjusted hazard ratio [HR] for RCB 2/3 compared to 0/1 was 5.64, 95% confidence interval 3.19-9.99, p<0.0001, Table).

Conclusions:
In this large multi-institutional prospective clinical trial of patients with high-risk breast cancer completing NAC over the last decade we found no increased risk of LRR following BCS compared to mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that breast conservation surgery is an excellent surgical option for patients after NAC in appropriately selected patients.

Table 1. Multivariate Cox Proportional Hazards Regression for Local Recurrence Outcome

Variables	HR (95%CI)	P-value
Age Group
<50 yrs	Reference
>=50 yrs	0.84 (0.55, 1.30)	0.44
Tumor Subtype
HR+Her2-	Reference
HR-Her2-	2.56 (1.58, 4.13)	0.0001
Her2+	1.15 (0.61, 2.18)	0.66
Clinical Stage
II	Reference
III	1.56 (0.98, 2.49)	0.06
Breast Surgery
BCS	Reference
Mastectomy	0.94 (0.60, 1.47)	0.78
RCB Class
0/1	Reference
2/3	5.64 (3.19, 9.99)	<.0001

HR: Hazard Ratio, CI: Confidence Interval.


Figure 1. Kaplan-Meier Plot Stratified by Surgery and RCB Category for Local Recurrence

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