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IntroductionIn the South African Breast Cancer and HIV Outcomes (SABCHO) study, we previously found that breast cancer patients living with HIV and treated with neoadjuvant chemotherapy achieve lower rates of complete pathologic response than patients without HIV. We now assess the impact of comorbid HIV on receipt of timely and complete neoadjuvant and adjuvant chemotherapy.Materials and MethodsSince June 2015, the SABCHO study has collected data on women diagnosed with breast cancer at 6 South African hospitals. We selected a sample of participants with stages I-III cancer who received ≥2 doses of neoadjuvant or adjuvant chemotherapy. Data on chemotherapies prescribed and received, filgrastim receipt, and laboratory values measured during treatment were captured from patients’ medical records. We calculated the mean relative dose intensity (RDI) for all prescribed chemotherapies. We tested for association between full regimen RDI and HIV status, using linear regression to control for demographic and clinical covariates, and for association of HIV with laboratory abnormalities.ResultsThe 166 participants living with HIV and 159 without HIV did not differ in median chemotherapy RDI: 0.89 (interquartile range (IQR) 0.77-0.95) among those living with HIV and 0.87 (IQR 0.77-0.94) among women without HIV. Patients living with HIV experienced more grade 3+ anemia and leukopenia than those without HIV (anemia: 10.8% vs. 1.9%, P = .001; leukopenia: 8.4% vs. 1.9%, P = .008) and were more likely to receive filgrastim (24.7% vs. 10.7%, P = .001).ConclusionsHIV status did not impact neoadjuvant or adjuvant chemotherapy RDI, although patients with breast cancer living with HIV experienced more myelotoxicity during treatment.

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.

ABP 980 (KANJINTI™, Amgen, Thousand Oaks, CA, USA; Amgen Europe B.V., The Netherlands) is a biosimilar to trastuzumab (Herceptin®), a monoclonal antibody that selectively binds human epidermal growth factor receptor-2 (HER2). Here we provide a brief overview of the totality of evidence (including analytical [structural and functional] characterization, nonclinical evaluation, and human pharmacokinetic [PK], pharmacodynamic, and clinical assessment comparing ABP 980 with trastuzumab reference product [RP]) that supported the approval of ABP 980, along with practical considerations on the reconstitution and use of the lyophilized product to ensure safe and effective administration. ABP 980 has been shown to be highly similar to the RP, with similar mechanism of action, binding, and potency. Key PK parameters, geometric means ratio (GMR [90% CI]) of Cmax and AUCinf, are comparable and within the equivalence margin of 0.80 to 1.25 (ABP 980: 1.04 [0.99–1.08] versus trastuzumab US: 1.06 [1.00–1.12]; ABP 980: 0.99 [0.95–1.03] versus trastuzumab EU: 1.00 [0.95–1.06]). No clinically meaningful differences were found between ABP 980 and RP in a comparative clinical trial in patients with HER2-positive early breast cancer. Pathological complete response—ABP 980: 48% versus RP: 41% (risk difference [RD], 90% CI: 7.3%, 1.2–13.4; relative risk [RR], 90% CI: 1.188, 1.033–1.366). Sensitivity analyses per central pathology review—ABP 980: 48%; RP: 42% (RD: 5.8%, −0.5 to 12.0; RR: 1.142, 0.993–1.312), with RD and RR falling within predefined equivalence margins. Similar to trastuzumab RP, KANJINTI™ is supplied as a sterile, lyophilized cake to be reconstituted with bacteriostatic water for injection (BWFI) for multiple-dose injection or sterile WFI for single use. Stability data support storage of reconstituted solution at 2–8°C (36–46°F), up to 28 days. Reconstituted solution can be diluted in infusion bags containing 0.9% saline and stored for up to 24 h prior to intravenous administration. Electronic supplementary material The online version of this article (10.1007/s40487-020-00129-x) contains supplementary material, which is available to authorized users.

Although the human epidermal growth factor receptor 2 (HER2) blocker trastuzumab is generally well tolerated, cardiotoxicity can be an important therapeutic limitation.Objective.In this prespecified analysis, we compared the cardiac safety of the trastuzumab biosimilar ABP 980 (KANJINTI™) and the trastuzumab reference product (RP; Herceptin®) in the phase III LILAC study (ClinicalTrials.gov identifier NCT01901146).Methods.In the neoadjuvant phase of LILAC, after run-in chemotherapy, 725 patients were randomized 1:1 to ABP980 (n = 364) or trastuzumab RP (n = 361) plus paclitaxel (every 3weeks [Q3W] or every week [QW]) for four cycles. After surgery, patients continued treatment Q3W for up to 1year; ABP980-treated patients continued ABP980 (ABP980/ABP980;n = 364), and trastuzumab RP-treated patients either continued on the RP (trastuzumab RP/trastuzumab RP;n = 190) or switched to ABP980 (trastuzumab RP/ABP980;n = 171). Cardiac safety was monitored by computerized 12-lead electrocardiogram, and left ventricular ejection fraction (LVEF) was assessed by two-dimensional (2D) echocardiogram. LVEF decline was defined as LVEF value decrease from study baseline by ≥ 10 percentage points and to&thinsp

Simple Summary In the USA and Europe, questionnaires that allow patients to directly report chemotherapy side effects can improve their quality of life and clinical outcomes. No similar tools exist for Africa, so we aimed to design and validate a paper-based tool for use in oncology clinics in South Africa: The Patient Reported Symptoms-South Africa (PRS-SA) survey. The PRS-SA included questions on overall feelings of distress and severity of 11 common chemotherapy side effects. By comparing responses to the PRS-SA to responses to other quality of life questionnaires and to patients’ performance status, we found the PRS-SA to be valid and responsive for measuring all included symptoms. Compared to a standard instrument for measuring depression and anxiety, the PRS-SA’s distress thermometer had 88% sensitivity and 55% specificity for identifying distress. The PRS-SA may be a useful tool for efficiently assessing distress and chemotherapy symptoms in South Africa’s overburdened public oncology clinics. Abstract Patient-reported outcome measures (PROM) for monitoring treatment toxicity improve quality of life (QoL) and clinical outcomes. However, no such PROMs exist for sub-Saharan African cancer patients. We aimed to validate the Patient Reported Symptoms-South Africa (PRS-SA) survey, a novel PROM for measuring distress and chemotherapy-related symptoms in South African cancer patients. We enrolled patients at the oncology clinic at Charlotte Maxeke Hospital, Johannesburg. At three separate visits, participants simultaneously completed the PRS-SA survey and several previously validated questionnaires. We constructed a receiver operator characteristics curve for distress levels predicting a Hospital Anxiety and Depression Scale (HADS) score ≥15. We evaluated construct validity for symptom items by comparing severity to the EORTC Core Quality of Life Questionnaire (QLQ-C30) summary score (Pearson correlation tests) and ECOG performance status (Mann–Whitney U tests). We assessed symptom item responsiveness by comparing change in severity to change in QLQ-C30 summary score and comparing standardized mean scores with negative, no, or positive change on the Global Impression of Change (GIC) questionnaire (Jockheere–Terpstra trend test). Overall, 196 participants with solid tumors completed instruments. A distress score of 4 had 82% sensitivity and 55% specificity for clinical depression/anxiety. All symptom items showed construct validity by association with either QLQ-C30 score or performance status (highest p = 0.03). All but cough showed responsiveness to change in QLQ-C30 score (highest p = 0.045). In South African cancer patients, the PRS-SA’s stress scale behaves similarly to the distress thermometer in other populations, and the symptom items demonstrated construct validity and responsiveness. Of note, 46% and 74% of participants who completed the PRS-SA in English or isiZulu, respectively, required assistance reading half or more of the instrument.

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.

Aim To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. Patients and methods 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). Results At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74–1.00) for L+T versus T and 0.93 (95% CI, 0.81–1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70–1.06) for L+T versus T and 0.88 (95% CI, 0.71–1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64–1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69–1.00; 6-yr DFS% = 83% versus79%)] subgroups. Conclusion T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. Trial Registration clinicaltrials.gov Identifier NCT00490139 .

Objectives Publication in 2013 of the first Secondary Cancer cohort study returned attention to liver transplant for nonresectable colorectal cancer, demonstrating excellent outcomes for a procedure that was historically contraindicated. The Wits Donald Gordon Medical Centre in Johannesburg, South Africa, hosts the largest liver transplant program in subSaharan Africa. The persistent shortage of deceased donor organs in our setting has compelled us to innovate solutions unique to our context, which allows us to perform as many transplants as possible and maximize our resource utilization. Therefore, we initiated a research study to transplant organs in patients with nonresectable colorectal carcinoma with expanded criteria using marginal deceased donor organs that would otherwise have been discarded. Materials and methods Institutional Review Board approval was obtained for this study. We used criteria from the 2013 Secondary Cancer cohort study to determine eligibility of patients with nonresectable colorectal carcinoma for liver transplant. Unlike the study from 2013, we utilized expanded criteria and marginal liver allografts for transplant. Results Five patients have undergone liver transplant for nonresectable colorectal carcinoma. At a median follow-up of 36 months (range, 10-52 months), 4 of the 5 (80%) patients are alive. The patient who died had progressive disease on chemotherapy pretransplant and was the only patient who tested positive for the Kirsten rat sarcoma viral oncogene homolog mutant. Recurrence occurred in all patients at a median time of 6 months after transplant (range, 3-13 months). Conclusions To our knowledge, this is the only published case series of patients undergoing liver transplant for nonresectable colorectal carcinoma in Africa and is internationally unique in its use of expanded criteria and marginal grafts for this type of transplant. Despite the use of such grafts in our recipients, thus far, these outcomes align with those of the 2013 Secondary Cancer cohort studies from Norway.

Purpose: The state of limited resource settings that Coronavirus (COVID-19) pandemic has created globally should be taken seriously into account especially in healthcare sector. In oncofertility, patients should receive their fertility preservation treatments urgently even in limited resource settings before initiation of anticancer therapy. Therefore, it is very crucial to learn more about oncofertility practice in limited resource settings such as in developing countries that suffer often from shortage of healthcare services provided to young patients with cancer. Methods: As an extrapolation during the global crisis of COVID-19 pandemic, we surveyed oncofertility centers from 14 developing countries (Egypt, Tunisia, Brazil, Peru, Panama, Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, and India). Survey questionnaire included questions on the availability and degree of utilization of fertility preservation options in case of childhood cancer, breast cancer, and blood cancer. Results: All surveyed centers responded to all questions. Responses and their calculated oncofertility scores showed different domestic standards for oncofertility practice in case of childhood cancer, breast cancer, and blood cancer in the developing countries under limited resource settings. Conclusions: Medical practice in limited resource settings has become a critical topic especially after the global crisis of COVID-19 pandemic. Understanding the resources necessary to provide oncofertility treatments is important until the current COVID-19 pandemic resolves. Lessons learned will be valuable to future potential worldwide disruptions due to infectious diseases or other global crises.

ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, arandomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant-adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.

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.

172 Background: In the USA, use of patient-reported outcome (PRO) instruments for monitoring treatment toxicity has been associated with improved patient quality of life (QoL) and clinical outcomes. No similar PRO tools exist for the African cancer patients. We aimed to validate the Patient Reported Symptoms – South Africa (PRS-SA) survey, a novel PRO tool designed to measure subjective stress and symptoms in South African (SA) cancer patients receiving chemotherapy. Methods: We enrolled patients receiving chemotherapy at the oncology clinic at Charlotte Maxeke Hospital, Johannesburg. At 3 separate visits, participants completed the PRS-SA survey, which allowed reporting of stress on a numerical ranking scale (range 0-10) and severity of 11 common chemotherapy-related symptoms (i.e., pain, fatigue, fever, dyspnea, cough, mucositis, nausea, vomiting, diarrhea, constipation, and neuropathy) using lay language descriptions corresponding to Common Terminology Criteria for Adverse Events grades. They simultaneously completed the EORTC Core Quality of Life Questionnaire (QLQ-C30), the Global Impression of Change (GIC) questionnaire, and the Hospital Anxiety and Depression Scale (HADS). All instruments were offered in English and isiZulu. We constructed a receiver operator characteristics (ROC) curve for stress scale values and a total HADS score ≥15, representing clinical depression/anxiety. We evaluated construct validity for each symptom item by comparing symptom severity to the simultaneous QLQ-C30 summary score (Pearson correlation tests) and ECOG performance status (PS) (Mann-Whitney U tests). We assessed symptom item responsiveness by comparing change in severity across visits to change in QLQ-C30 summary score and comparing standardized mean symptom scores in those reporting negative, no, or positive change on the GIC using a Jockheere-Terpstra trend test. Results: Overall, 196 participants completed instruments at visit 1, 173 at visit 2, and 150 at visit 3. Area under the ROC curve for stress score was 0.76, and a score of 4 had 82% sensitivity and 55% specificity for clinical depression/anxiety. All symptom items showed construct validity by association with QLQ-C30 score (all p-values < 0.0001), and all but mucositis showed validity by association with ECOG PS (highest p = 0.03). All but cough showed responsiveness to change in QLQ-C30 score (highest p = 0.045), and the standardized mean in symptom scores demonstrated a trend across negative, neutral, and positive GIC scores (p = 0.03). Conclusions: In SA cancer patients, the PRS-SA’s stress scale behaves similarly to the distress thermometer in other populations, and the symptom items demonstrated construct validity and responsiveness. Further research should address implementation of the PRS-SA in the clinical setting for monitoring cancer treatment-related toxicity and its impact of patients’ QoL and outcomes.

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

PURPOSE Oncofertility practice continues to grow in developing countries despite the lack of health care services, especially those related to cancer care. The purpose of this study is to further explore oncofertility practice in these countries and identify opportunities for field-wide coalescence. METHODS We generated a survey to learn more about oncofertility practice in nine developing countries within our Oncofertility Consortium Global Partners Network—Mexico, Colombia, Guatemala, Argentina, Chile, Nigeria, South Africa, Saudi Arabia, and India. Their responses were collected, reviewed, and discussed. RESULTS Surveyed centers from the nine developing countries continue to experience a similar set of common challenges, including a lack of awareness among providers and patients, cultural and religious constraints, lack of insurance coverage and funding to help to support oncofertility programs, and high out-of-pocket costs for patients. Despite these barriers, many opportunities exist and there is great potential for the future. CONCLUSION The current need is to unify the new technologies and best practices that emerge from rural communities and developing countries with those in large metropolitan cities, both domestically (US based) and abroad, into a functional unit: the Oncofertility Professional Engagement Network. The Oncofertility Professional Engagement Network will bridge the gap between domestic and international programs to establish a strong global network in which members share resources, methodologies and experiences and further build cultural competency.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

557 Background: Although trastuzumab is generally well-tolerated, cardiotoxicity is the main limitation in its use, leading to a severe heart failure in 2-4% of patients in adjuvant trials. In the phase 3 LILAC trial, trastuzumab biosimilar ABP 980 demonstrated similar efficacy, safety, and immunogenicity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer. Here we report analyses comparing cardiac safety of ABP 980 and RP. Methods: In the neoadjuvant phase, all 725 patients received 4 cycles of chemotherapy with epirubicin + cyclophosphamide Q3W and were then randomized 1:1 to ABP 980 (n = 364) or RP (n = 361) with a loading dose of 8 mg/kg, then 6 mg/kg IV Q3W for 3 cycles plus paclitaxel Q3W (4 cycles) or QW (12 cycles). After surgery, patients received investigational product (IP) Q3W for up to 1 year; ABP 980-treated patients continued ABP 980, and RP-treated patients either continued RP (n = 190) or switched to ABP 980 (RP/ABP 980; n = 171). AEs were assessed every 3 weeks and cardiac safety every 3 months. Cardiac safety was monitored by computerized 12-lead ECG; LVEF was assessed by 2D ECHO. LVEF decline was defined as LVEF value decrease from study baseline by ≥10 percentage points and to < 50%. Results: Treatment groups were well balanced with regard to IP disposition. Over the entire study, 22 (3.1%) patients had LVEF decline by ≥10 percentage points compared to baseline and to < 50%; no meaningful between-group differences were observed (ABP 980:10/359 [2.8%], RP: 6/184 [3.3%], RP/ABP 980: 6/171 [3.5%]). The incidence of cardiac AEs was low and comparable in treatment groups. One grade 3 cardiac failure event was reported in the RP/ABP 980 arm; another in the RP arm was coincident with LVEF decline. No patient discontinued IP during adjuvant phase because of cardiac failure. Conclusions: These pre-specified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and RP with respect to cardiac safety. The incidence of LVEF decline was consistent with the known cardiac safety profile of the RP. No new cardiac safety signals were observed whether patients were on ABP 980 or switched from RP to ABP 980. Clinical trial information: NCT01901146.

Importance Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. Objective To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. Design, Setting, and Participants In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Interventions Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m 2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. Main Outcome and Measures The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. Results The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed. Conclusions and Relevance In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm. Trial Registration clinicaltrials.gov Identifier:NCT00915018

583Background: The phase 3 LILAC Study compared ABP 980 with trastuzumab (TRAS) on pathologic complete response (pCR) in women with HER2+ early breast cancer. The primary efficacy results, based on...

To determine if concomitant administration of docetaxel plus zosuquidar.3HC1 can prolong progression-free survival in patients with metastatic breast cancer. A randomized, double-blind, multicenter, placebo-controlled clinical trial comparing docetaxel plus 500 mg zosuquidar.3HCl (DZ) with docetaxel plus placebo (DP). A total of 170 patients were enrolled and randomly assigned to treatment. The median age was 53 years (range, 31–74 years). 81.7% of patients had prior chemotherapy in the adjuvant setting and 18.3% in the neoadjuvant setting. The median progression-free survival time was statistically different between groups [7.2 months (DZ) vs. 8.3 months (DP)]. Once the stratification factor relative to progression following prior chemotherapy was considered, no significant treatment difference existed. The combination of zosuquidar.3HCl plus docetaxel is safe. The analysis of efficacy data is complex, but it can be concluded that there is no difference in progression-free survival, overall survival, or response rate in the study as a whole.

In the present study the green alga Scenedesmus obliquus was used to assess the effects of high salinity (high NaCl-concentration) on the structure and function of the photosynthetic apparatus and the possibility for alleviation by exogenous putrescine (Put). Chlorophyll fluorescence data revealed the range of the changes induced in the photosynthetic apparatus by different NaCl concentrations, which altogether pointed towards an increased excitation pressure. At the same time, changes in the levels of endogenous polyamine concentrations, both in cell and in isolated thylakoid preparations were also evidenced. Certain polyamine changes (Put reduction) were correlated with changes in the structure and function of the photosynthetic apparatus, such as the increase in the functional size of the antenna and the reduction in the density of active photosystem II reaction centers. Thus, exogenously added Put was used to compensate for this stress condition and to adjust the above mentioned changes, so that to confer some kind of tolerance to the photosynthetic apparatus against enhanced NaCl-salinity and permit cell growth even in NaCl concentrations that under natural conditions would be toxic.

Systemic neoadjuvant chemotherapy is utilized along with surgery and radiotherapy for the management of patients with locally advanced breast cancer. The backbone of current chemotherapy regimens include anthracyclines and taxanes given either sequentially or concurrently for up to 8 cycles. Neoadjuvant treatment benefits include in vivo assessment of response to treatment with reduction in the extent of primary and regional metastases. Neoadjuvant chemotherapy for operable breast cancer is used in women who desire breast conservation surgery who are not candidates for such treatment at the time of the diagnosis. The use of neoadjuvant treatment in patients, who present with operable breast cancer, shows equivalent survival outcome compared with adjuvant breast cancer treatment. Several prospective studies have evaluated the role of trastuzumab in combination with neoadjuvant chemotherapy in patients with Her2-positive disease. The addition of trastuzumab to neoadjuvant chemotherapy is associated with improvement of the complete clinical and pathological complete response to therapy and significantly improved event-free survival and overall survival. Dual Her2 blockade is emerging as a new approach to improve pathological complete response rates and therefore survival. To date, in triple-negative breast cancer, there are no predictive markers to identify potential treatment targets. Triple-negative patients who achieve a pathological complete response have more favorable outcome compared with those with residual disease following neoadjuvant treatment. The choice of optimal chemotherapy regimen and the duration of treatment have been studied extensively in the neoadjuvant setting. No consensus has been developed thus far. Following work done with anthracycline and CMF treatments in neoadjuvant chemotherapy, recent studies in locally advanced breast cancer focus on the addition of new and target agents. All of these trials are based on well-established regimes used in the adjuvant setting. Successful use of neoadjuvant chemotherapy requires a coordinated multidisciplinary approach.

610 Background: This large randomized open-label phase 2 trial compared the efficacy and safety of Neratinib (N), the irreversible pan-HER tyrosine kinase inhibitor, + Paclitaxel (P) vs Trastuzumab...

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumours, both clinically and pathologically. These cancers are characterised by the lack of expression of the hormone receptors oestrogen receptor (OR) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomised trials. Numerous studies have now shown that TNBC has significantly higher pathological complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathological diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant and metastatic setting, including an assessment of future directions of treatment.

The prophylaxis of chemotherapy-induced nausea and vomiting benefited greatly from the introduction of neurokinin-1 (NK1) receptor antagonists (RAs). Current emesis guidelines recommend that NK1 receptor antagonists be combined with 5-HT3 receptor antagonists and dexamethasone for highly emetic chemotherapy and moderately emetic chemotherapy. The first such medication, aprepitant, was approved in the US in 2003. Fosaprepitant, an intravenous prodrug of aprepitant, is also available as a single dose on day 1 in combination with other antiemetics. Fosaprepitant is rapidly converted to the active aprepitant and exhibits a similar half-life to orally administered aprepitant. In addition, receptor-binding studies have shown aprepitant striatal NK1 receptor occupancy of 90 % for over 48 hours after exposure. These characteristics may allow aprepitant, fosaprepitant and the newer NK1 RAs to be administered in a single dose on day 1. Olanzapine may prove to be a novel approach in the treatment of CINV, particularly in the management of nausea.