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Introduction In the South African Breast Cancer and HIV Outcomes (SABCHO) study, early-stage breast cancer patients living with HIV, compared to their HIV-negative counterparts, demonstrated higher overall mortality and lower rates of pathologic complete response if treated with neoadjuvant chemotherapy. We aimed to determine if comorbid HIV also impacted receipt of timely and complete neoadjuvant and adjuvant chemotherapy. Methods We retrospectively identified Black, stage I-III SABCHO participants diagnosed with breast cancer from June 2015 to July 2019 and who received at least 2 doses of neoadjuvant or adjuvant chemotherapy at either Charlotte Maxeke Johannesburg Academic Hospital (Gauteng) or Grey’s Hospital (KwaZulu-Natal). Data on the originally prescribed chemotherapy regimen and the dose and timing of all received chemotherapy was extracted from patients’ medical records, as well as values from all complete blood counts and metabolic panels performed during treatment. Relative dose intensity (RDI) was calculated for each agent in the prescribed regimen with the mean RDI of all agents representing the RDI of the full regimen. We assessed for associations between full regimen RDI and HIV status using a multivariable linear regression model that included demographic and clinical covariates also shown to impact RDI. We also compared rates of myelosuppression, alkaline phosphatase elevation, and creatinine elevation using linear regression. Using previously collected survival data, we compared overall mortality based on overall RDI above or below 0.85. Results We analyzed data from 325 eligible subjects, 166 of whom were living with HIV. No differences based on HIV status were appreciated in the prescribed chemotherapy regimens. For women without HIV median RDI was 0.87 (interquartile range (IQR) 0.77-0.94) and, in those living with HIV, it was 0.89 (IQR 0.77-0.95). HIV status showed no significant association with RDI on multivariable analysis, and the only patient characteristics associated with RDI were estrogen/progesterone receptor (ER/PR) and HER2 status. Patients living with HIV experienced more CTCAE v5.0 grade 3+ anemia and leukopenia than those without HIV (anemia: 10.8% vs 1.9%, p=0.001; leukopenia: 8.4% vs 1.9%, p=0.008) and were more likely to receive at least one dose of filgrastim (24.7% vs 10.7%, p=0.001). Receipt of RDI greater or less than 0.85 did not predict overall mortality in the full cohort or HIV status subgroups. A trend towards improved survival with RDI greater than 0.85 was seen among the 69 participants with ER/PR negative disease (hazard ratio: 0.60, 95% confidence interval: 0.30-1.21, p = 0.15). Conclusions Neoadjuvant and adjuvant chemotherapy RDI did not differ by HIV status among women in the SABCHO study, although women living with HIV experienced more myelotoxicity during treatment. Efforts to reduce chemotherapy dose reduction and delays should target all South African breast cancer patients. Citation Format: Daniel S. O’Neil, Oluwatosin A Ayeni, Hayley A. Farrow Woolridge, Wenlong Carl Chen, Georgia Demetriou, Ines Buccimazza, Sharon Cacala, Maureen Joffe, Michael Antoni, Gilberto Lopes, Yoanna Pumpalova, Witness Mapanga, Judith S. Jacobson, Katherine D. Crew, Alfred I. Neugut, Paul Ruff, Herbert Cubasch. The Impact of Comorbid HIV infection on Neoadjuvant and Adjuvant Chemotherapy Relative Dose Intensity in South African Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-01-03.

Pathological complete response (pCR) after neoadjuvant therapy is an accepted surrogate endpoint for breast cancer registration trials and is a strong prognostic biomarker especially in high-risk tumor biology. The LILAC study, a comparative trial for the trastuzumab biosimilar ABP 980, was the first international multicenter neoadjuvant breast cancer trial using local and central pathology review for pCR. Here we report concordance between local and central review for the most commonly used pCR definitions. This study included 725 patients with early HER2-positive breast cancer, comparing neoadjuvant ABP 980 and trastuzumab reference product (RP) in combination with anthracycline and taxane-containing chemotherapy. Equivalence of both arms was defined at a significance level of 0.05 by comparing the 2-sided 90% confidence interval (CI) for the risk difference (RD) of pCR between ABP 980 and RP within a predefined margin (-13%, 13%) using definition 2 as described below. pCR was evaluated in local laboratories and in a central laboratory blinded to the local result. The purpose of the independent, central review was to reduce the inter-pathologist variability and provide a more consistent assessment. Central review was performed by 2 independent pathologists; in cases of discordance the specimen was reviewed and decided by a third pathologist (adjudicator). The pCR definition in the primary analysis was no invasive breast cancer in breast and axillary nodes, regardless of ductal carcinoma in situ (DCIS). No invasive tumor in the breast was pCR definition 1, no invasive breast cancer in breast and axillary nodes regardless of DCIS was pCR definition 2, and no invasive breast cancer in breast and axillary nodes and absence of DCIS was pCR definition 3. The RDs and CIs were evaluated for local and central pCR review for all 3 pCR definitions. The results of the neoadjuvant LILAC study have been reported previously, demonstrating no clinically meaningful differences between ABP 980 and RP in HER2-positive early breast cancer. Of the 696 subjects who underwent surgery and had specimens evaluable for pCR review by the local pathologists, 669 specimens were available for central review. Rates of pCR in the local review were 51.1% (ABP 980) and 45% (RP) for definition 1, 48% (ABP 980) and 40.5% (RP) for definition 2, and 37.7% (ABP 980) and 29.6% (RP) for definition 3. The corresponding pCR rates in the central review were 51.3% and 47.3% for definition 1, 47.8% and 41.8% for definition 2, and 29.9% and 26.1% for definition 3. The CI for RD was within the predefined margins for pCR definition 1 in local and central review, whereas it exceeded the prespecified margin in local review for pCR definitions 2 and 3. In the central review the CI was within the margin for the pCR definitions 2 and 3, with the difference between local and central pathology review 1.6% for pCR definition 2 and 4.4% for pCR definition 3, respectively. RDs (90% CI) for all 3 pCR definitions are shown in the Table. The LILAC study demonstrated that a central pathology review for pCR is feasible in a large, international, multicenter neoadjuvant breast cancer trial. Our results show that concordance between local and central pathology can decrease with increasing complexity of the pCR definition. Based on the results, it may be justified to include a central pathology review in neoadjuvant multicenter breast cancer trials with strict pCR definitions. Citation Format: Hanz-Christian Kolberg, Marco Colleoni, Georgia Savva Demetriou, Patricia Santi, Hans Tesch, Yasuhiro Fujiwara, Vladimir Hanes. The importance of central pathology pCR review in an international multicenter neoadjuvant study in HER2 positive early breast cancer - Results of the ABP 980 LILAC trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-04.

Background: Analytical, functional, and pharmacokinetic similarity between the proposed biosimilar ABP 980 and trastuzumab (TRAS) has been shown. Similar efficacy and safety have also been demonstrated in the neoadjuvant phase of the phase 3 comparative clinical study. Here we focus on the safety and immunogenicity results from the adjuvant phase of this study. Methods: The objective of this study was to compare ABP 980 with TRAS in women with HER2 positive early breast cancer. After run-in anthracycline-based chemotherapy, patients were randomized 1:1 to intravenous ABP 980 or TRAS plus paclitaxel Q3W for 4 cycles. Surgery was completed 3-7 weeks after the last dose of neoadjuvant study drug. After surgery, patients who initially received TRAS were allocated to either continue TRAS (TRAS/TRAS arm) or undergo a single switch to receive ABP 980 (TRAS/980 arm) and patient who initially received ABP 980 continued to receive ABP 980 (980/980 arm) Q3W for up to 1 year. This report is based on safety data collected at the time of primary analysis, when all patients had completed the first post-surgery clinical visit or had withdrawn. The majority of patients had completed the study at the time of this analysis. Results: 725 patients were randomized; 364 and 361 patients were randomized to ABP 980 and TRAS, respectively, in the neoadjuvant phase. Following surgery, 349 patients in the 980/980 arm, 171 patients in the TRAS/TRAS arm, and 171 patients in the TRAS/980 arm entered the adjuvant phase. Adverse events (AEs) during the adjuvant phase are shown in Table 1; data from the neoadjuvant safety phase have been previously reported. Table 1 980/980 (N = 349)TRAS/TRAS (N = 171)TRAS/980 (N = 171)AE category, n (%) Any AE201 (57.6)89 (52.0)98 (57.3)Any grade ≥3 AE27 (7.7)10 (5.8)10 (5.8)Any fatal AE001 (0.6)Any serious AE14 (4.0)4 (2.3)4 (2.3)AEs of Interest, n (%) Infections and infestations46 (13.2)14 (8.2)21 (12.3)Neutropenia37 (10.6)16 (9.4)13 (7.6)Infusion reactions27 (7.7)10 (5.8)15 (8.8)Hypersensitivity11 (3.2)3 (1.8)7 (4.1)Pulmonary toxicity3 (0.9)2 (1.2)1 (0.6)Cardiac failure01 (0.6)1 (0.6)LVEF decline by ≥10% and to below 50%, n/N* (%)9/313 (2.9)3/154 (1.9)3/153 (2.0)LVEF = left ventricular ejection fraction; N* = Number of patients with data available One patient in the TRAS/980 arm developed binding antibodies during the adjuvant phase; this patient tested negative for neutralizing antibodies. In the neoadjuvant phase, 2 patients in the ABP 980 arm and 2 in the TRAS arm developed binding antibodies but tested negative for neutralizing antibodies. The percent of patients with disease progression or recurrence or death was 5.2% in the 980/980 arm, 5.3% in the TRAS/TRAS arm, and 2.9% in the TRAS/980 arm. The estimated hazard ratio from a stratified Cox proportional hazards regression model for 980/980 versus TRAS/TRAS was 1.01 (90% CI: [0.530, 1.930]) and for TRAS/980 versus TRAS/TRAS was 0.48 (90% CI: [0.181, 1.292]). Conclusions: Safety of ABP 980 is similar to TRAS in patients with HER2+ early breast cancer in both the neoadjuvant and adjuvant phases and consistent with the historical safety profile of TRAS. The immunogenicity profile of ABP 980 is low and consistent with TRAS. Citation Format: Kolberg H-C, Demetriou GS, Zhang N, Tomasevic Z, Hanes V. Safety results from a randomized, double-blind, phase 3 study of ABP 980 compared with trastuzumab in patients with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-10.