Recht, Abram

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

603 Background: Accurate prediction of pathologic complete response (pCR) after preoperative therapy for HER2-positive (HER2+) breast cancer can help triage patients to immediate surgery vs additional preoperative therapy. Pre-surgery (i.e., after neoadjuvant therapy) imaging studies may help estimate the likelihood of pCR. In EA1181, patients (pts) with stage II-IIIA HER2+ breast cancer received four cycles of preoperative taxane, trastuzumab, and pertuzumab (THP×4). Pre-surgery imaging was required, though the specific imaging modality was not mandated. Here, we report the accuracy of pre-surgery breast MRI to predict pCR (ypT0/Tis, ypN0). Methods: Among 2,141 pts treated with THPx4, 1,378 had pre-surgery breast MRI and were representative of the overall cohort, although T3 tumors were more common (16% vs 9%). MRI reports were available for 1,351 pts; all reports were centrally reviewed and classified as radiologic complete response (rCR; no residual tumor enhancement and normalization of lymph nodes, if applicable) or radiologic residual disease (rRD). Reports with indeterminate radiologic response were independently reviewed by two study radiologists blinded to pathology outcomes. Among pts with rCR who had pathologic residual disease (pRD), we also assessed the extent of residual disease by residual cancer burden (RCB) score. Among pts with rRD who had a pCR, we determined the proportion who only had residual ductal carcinoma in situ (DCIS). Results: See Table. Conclusions: After neoadjuvant therapy, preoperative MRI accurately predicted pCR in 86% of patients with HER2+/ER− disease and may help identify patients who can proceed directly to surgery. MRI is insufficient to predict pCR for pts with HER2+/ER+ disease, as only 55% with complete response on MRI had a pCR at surgery. A pre-surgery MRI that indicated residual disease was accurate in 80% of pts with HER2+/ER+ disease, but in only 45% of pts with HER2+/ER- cancer. Accurately predicting residual disease after THPx4 allows for consideration of additional therapy that may increase the chance of pCR. Combining imaging like MRI with other biomarkers, such as tissue-based markers or circulating tumor DNA, may improve prediction of pCR and facilitate personalization of treatment decisions in HER2+ breast cancer. All pts with pre-surgery MRI (n=1351)pCR rate overall in this cohort = 47% MRI result Pathology pCR pRD rCR 70.6% (341/483) 29.4%(142/483) 78% had RCB1 rRD 34%(295/868) 21% of 295 had DCIS only 66.01% (573/868) ER- (n=589)*Overall pCR rate in ER- subset = 68% MRI result Pathology pCR pRD rCR 86.1% (205/238) 13.9% (33/238) 85% had RCB1 rRD 55.3% (194/351) 19% of 194 had only DCIS 44.7% (157/351) ER+ (n= 762)*Overall pCR rate in ER+ subset = 31% MRI result Pathology pCR pRD rCR 55.5% (136/245) 44.5% (109/245) 76% had RCB1 rRD 19.5% (101/517) 26% of 101 had only DCIS 80.5% (416/517)

501 Background: EA1181 (NCT04266249) is a single-arm trial of neoadjuvant THP for patients with clinical anatomic stage II/III HER2+ breast cancer; patients with cT4 or cN3 disease were excluded . Assessing the primary endpoint, 3-year recurrence-free survival in patients with a pCR (ypT0/Tis, ypN0), requires longer follow-up. Here, we present results for the secondary objective of pCR rate and its relation to clinicopathologic factors and the HER2DX pCR likelihood score (Reveal Genomics) derived from gene expression and clinical features. Methods: Patients received 4 cycles of trastuzumab and pertuzumab (HP) with weekly paclitaxel (12 weeks) or docetaxel (q3w x 4), followed by surgery. Clinicopathologic features were assessed for all patients and HER2DX pCR score (stratified by ER status) was determined using the diagnostic biopsy in a representative subset of study participants. Results: 2175 patients were enrolled. Median age was 55 years (range 22-88 years); 58% had clinical stage IIA, 33% stage IIB, and 9% stage III. 45% had nodal involvement (mostly cN1). 781 tumors were HER2+/ER- and 1394 HER2+/ER+ (locally tested ). 2141 patients started THP, for whom the pCR rate was 44% overall, 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Disease progressed during THP in 16 patients (0.7%). The pCR rate varied inversely to the proportion of cells staining for ER among patients with HER2+/ER+ breast cancer: 1-10%+, 62.5%; 11-69%, 51.6%; ≥70%, 22.5% (p <0.001). The pCR rate was significantly associated with higher grade, especially in HER2+/ER+ disease. T and N stage did not significantly affect pCR rate. Among 569 patients assessed for the HER2DX pCR score, the pCR rate was significantly greater for patients with a higher vs lower score, regardless of ER status (Table). Further correlations and interactions will be presented. Conclusions: Neoadjuvant THP resulted in pCR in nearly two-thirds of pts with clinical stage II/III HER2+/ER- and in one-third with HER2+/ER+ breast cancer. There was no association with clinical stage. Lower ER expression and higher grade were associated with higher pCR rates. The HER2DX pCR score was a significant predictor of pCR, regardless of ER status. Clinical trial information: NCT04266249 . All Participants HER2+/ER- HER2+/ER+ # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) Evaluable Cohort 2141 44%(42-46%) 774 64%(60-67%) 1367 32%(30-35%) HER2DX Cohort 569 48%(44- 52%) 230 69% (63-75%) 339 34%(29-39%) HER2DX pCR-high score 182 (32%) 68%(60-74%) 147 (64%) 70% (62-77%) 36 (11%) 58%(41-74%) HER2DX pCR-medium score 161 (28%) 67% (59- 74%) 70 (30%) 74%(62- 84%) 89 (26%) 61%(50-71%) HER2DX pCR-low score 226 (40%) 19%(14- 25%) 13 (6%) 31%(9-61%) 214 (63%) 18%(13-24%) P-value HER2DX score <0.001 0.010 <0.001

Abstract Objective To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. Design Systematic review and meta-analysis. Data sources Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). Study selection Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). Data extraction Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration’s tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. Data synthesis Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran’s Q test and I 2 statistic. Network meta-analysis was used to integrate all available evidence. Main outcome measures The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. Results From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. Conclusions MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. Systematic review registration PROSPERO CRD42023460249.

Abstract Background: The ECOG E5194 study was a prospective trial designed to evaluate surgical excision (lumpectomy) without radiation for selected women with ductal carcinoma in situ (DCIS) of the breast with low risk clinical and pathologic features. Methods: Eligible patients were enrolled on two study cohorts (not randomized): (1) low or intermediate grade DCIS, tumor size &lt; 2.5 cm; or (2) high grade DCIS, tumor size &lt; 1.0 cm. Cohort assignment was based on pathology assessment from the treating institution. Protocol specifications included surgical excision of the DCIS tumor with a minimum negative margin width of at least 3 mm or no tumor on re-excision. Radiation treatment was not allowed. From April 1997 to October 2002, 665 evaluable patients were enrolled through ECOG or NCCTG (561 in Cohort 1; 104 in Cohort 2). Tamoxifen was optional (not randomized) beginning in May 2000, and was given to 30% of the patients. The primary study endpoint was the rate of developing an ipsilateral breast event (IBE), defined as local recurrence of DCIS or invasive carcinoma in the treated breast. The median follow-up was 12.3 years. We have previously reported 7-year results (L. Hughes, J Clin Oncol 27:5319, 2009; median follow-up 6.3 years; 66 IBE’s), and we herein provide 12-year results. Results: Median patient age was 60 years and 58 years for Cohort 1 and Cohort 2, respectively. Tumor size was &lt; 10 mm for 79% and 80% of patients, respectively. The minimum negative margin width was &gt; 5 mm for 64% and 69% of patients, respectively. There were 99 IBE’s, of which 51 (52%) were an invasive IBE. The IBE and invasive IBE rates increased over time in both cohorts (see Table). The 12-year rates of an IBE were 14.4% for Cohort 1 and 24.6% for Cohort 2 (p = 0.003), and for an invasive IBE, 7.5% and 13.4%, respectively (p = 0.08). No difference was seen for the 12-year rates of overall survival (84.0% vs 82.8%; p = .96) or contralateral breast events (6.7% vs 12.0%; p = 0.16). On multivariate analysis, study cohort (hazard ratio = 1.81; p = 0.01) and tumor size (p = 0.01) were statistically significant for an IBE, and study cohort was borderline statistically significant for an invasive IBE (p = 0.08). On central pathology review (75% of cases), neither grade nor comedo necrosis was associated with the risk of an IBE or invasive IBE (all p &gt; 0.15). Salvage treatment at the time of an IBE included mastectomy for 42% (31/74) and 64% (16/25) of the patients, respectively. Conclusions: For these selected patients with favorable DCIS based on clinical and pathologic characteristics treated with surgical excision without radiation, the rates of an IBE and an invasive IBE continued to increase through at least 12 years of follow-up. IBE Rates According To Study Cohort. Cohort 1 (Low or Intermediate Grade)Cohort 2 (High Grade)TimeIBEInvasive IBEIBEInvasive IBEAt 5 years6.0% (4.0%, 8.1%)2.7% (1.3%, 4.1%)15.0% (7.7%, 21.7%)5.3% (0.8%, 9.7%)At 7 years9.5% (7.0%, 12.0%)4.8% (2.9%, 6.6%)18.2% (10.6%, 25.8%)7.6% (2.2%, 13.0%)At 10 years12.5% (9.5%, 15.4%)6.4% (4.2%, 8.6%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%)At 12 years14.4% (11.2%, 17.6%)7.5% (5.1%, 10.0%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%) Citation Format: Lawrence J Solin, Robert Gray, Lorie L Hughes, William C Wood, Mary Ann Lowen, Sunil Badve, Frederick L Baehner, James N Ingle, Edith A Perez, Abram Recht, Joseph Sparano, Kathy Miller, Nancy E Davidson. Local excision without radiation for ductal carcinoma in situ: 12-year results from the ECOG E5194 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-01.

PurposeTo determine the risk of ipsilateral breast events in patients with ductal carcinoma in situ (DCIS) treated with local excision without irradiation.Patients and MethodsPatients with either low- or intermediate-grade DCIS measuring 2.5 cm or smaller, or high-grade DCIS measuring 1 cm or smaller who had microscopic margin widths of 3 mm or wider and no residual calcifications on postoperative mammograms were eligible for a prospective trial conducted from 1997 to 2002 by the Eastern Cooperative Oncology Group and North Central Cancer Treatment Group. Patients entered in 2000 and later could take tamoxifen if they wished. Median age at last surgery for the entire population was 60 years (range, 28 to 88 years), and median tumor sizes in the two strata were 6 mm and 5 mm, respectively.ResultsWith a median follow-up of 6.2 years, the 5-year rate of ipsilateral breast events in the 565 eligible patients in the low/intermediate grade stratum was 6.1% (95% CI, 4.1% to 8.2%). With a median follow-up of 6.7 years, this incidence for the 105 eligible patients in the high-grade stratum was 15.3% (95% CI, 8.2% to 22.5%).ConclusionRigorously evaluated and selected patients with low- to intermediate-grade DCIS with margins 3 mm or wider had an acceptably low rate of ipsilateral breast events at 5 years after excision without irradiation. Patients with high-grade lesions had a much higher rate, suggesting that excision alone is inadequate treatment. Further follow-up is necessary to document long-term results.