The Impact of HIV Infection on Neoadjuvant and Adjuvant Chemotherapy Relative Dose Intensity in South African Patients with Breast Cancer.

INTRODUCTION: In 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 METHODS: Since 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. RESULTS: The 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). CONCLUSIONS: HIV status did not impact neoadjuvant or adjuvant chemotherapy RDI, although patients with breast cancer living with HIV experienced more myelotoxicity during treatment.

When and how do I use neoadjuvant chemotherapy for breast cancer?

OPINION STATEMENT: 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.

Totality of Evidence Supporting the Use of ABP 980, a Trastuzumab Biosimilar: Practical Considerations.

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.

Validating an Instrument for Direct Patient Reporting of Distress and Chemotherapy-Related Toxicity among South African Cancer Patients.

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.

Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D).

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.

Liver Transplant for Nonresectable Colorectal Cancer Liver Metastases in South Africa: A Single-Center Case Series.

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 sub-Saharan 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.

Cardiac Safety of the Trastuzumab Biosimilar ABP 980 in Women with HER2-Positive Early Breast Cancer in the Randomized, Double-Blind, Active-Controlled LILAC Study.

INTRODUCTION: 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 ABP 980 (n = 364) or trastuzumab RP (n = 361) plus paclitaxel (every 3 weeks [Q3W] or every week [QW]) for four cycles. After surgery, patients continued treatment Q3W for up to 1 year; ABP 980-treated patients continued ABP 980 (ABP 980/ABP 980; n = 364), and trastuzumab RP-treated patients either continued on the RP (trastuzumab RP/trastuzumab RP; n = 190) or switched to ABP 980 (trastuzumab RP/ABP 980; 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 < 50%. RESULTS: Over the entire study, 22 (3.1%) patients had protocol-defined LVEF decline; no meaningful between-group differences were observed (ABP 980/ABP 980: 2.8%; trastuzumab RP/trastuzumab RP: 3.3%; trastuzumab RP/ABP 980: 3.5%). The incidence of cardiac adverse events was low and comparable in the treatment groups. One grade 3 cardiac failure event reported in the trastuzumab RP/ABP 980 arm, and another in the trastuzumab RP/trastuzumab RP arm, were coincident with LVEF decline. One patient discontinued the investigational product during the adjuvant phase because of cardiac failure. CONCLUSION: These prespecified analyses confirm the tolerability of ABP 980 and demonstrate clinical similarity of ABP 980 and trastuzumab RP with respect to cardiac safety. No new cardiac safety signals were observed whether patients were receiving ABP 980 or switched from the RP to ABP 980.

Barriers and Opportunities of Oncofertility Practice in Nine Developing Countries and the Emerging Oncofertility Professional Engagement Network.

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.

Barriers and Opportunities of Oncofertility Practice in Nine Developing Countries and the Emerging Oncofertility Professional Engagement Network.

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.

Totality of Scientific Evidence in the Development of ABP 980, a Biosimilar to Trastuzumab.

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 ABP 980 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, a randomized 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.

Salt stress impact on the molecular structure and function of the photosynthetic apparatus--the protective role of polyamines.

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.

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.

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/m2 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.