Clinical outcomes of tamoxifen (TAM) treatment show wide interindividual variability. Comedications and genetic polymorphisms of enzymes involved in TAM metabolism contributes to this variability. Drug-drug and drug-gene interactions have seldom been studied in African Black populations. We evaluated the effects of commonly co-administered medicines on TAM pharmacokinetics in a cohort of 229 South African Black female patients with hormone-receptor positive breast cancer. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in TAM metabolism, including the variants CYP2D6*17 and *29, which have been mainly reported in people of African descent. TAM and its major metabolites, N-desmethyltamoxifen (NDM), 4-OH-tamoxifen, and endoxifen (ENDO), were quantified in plasma using the liquid chromatography-mass spectrometry. The GenoPharm open array was used to genotype CYP2D6, CYP3A5, CYP3A4, CYP2B6, CYP2C9, and CYP2C19. Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration (P < 0.001 and P < 0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO metabolic ratios but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of ENDO. This study also suggests a low risk of drug-drug interaction in patients with breast cancer on TAM.
Oral chemotherapy drug development and use has increased, and evidence in the literature suggests variability in practices nationally. Thus, there is a need for continuous review of the process of oral chemotherapy administration that focuses on improving adherence to national standards.
e19220 Background: Many barriers exist to delivering comprehensive breast cancer care in low-income countries. We examined sociodemographic factors associated with treatment completion among women receiving care for breast cancer at Butaro Cancer Center of Excellence (BCCOE), Rwanda’s first public cancer facility. Methods: We retrospectively measured treatment completion rates in women with early and locally advanced breast cancer diagnosed at BCCOE between July 1, 2012 and December 31, 2016. We defined treatment completion as receipt of surgery, 4 cycles of chemotherapy, and initiation of hormonal therapy for estrogen receptor positive (ER+) breast cancer. We used logistic regression to examine associations between socio-demographic and clinical factors and treatment completion. Travel time was estimated using a geographic information systems model using the WHO tool AccessMod 5.0. Results: Of 212 eligible women, 138 (65%) had surgery and 141 (66%) received 4 cycles of chemotherapy. Among 139 women with ER+ cancer, 59% initiated hormonal therapy. Overall 56% received all indicated treatment including surgery, chemotherapy, and hormonal therapy (if ER positive); 44% did not complete indicated treatment. Women who lived closer to the hospital ( <50 minutes travel time) were more likely than other women to complete treatment (OR 4.2; 95% CI 1.1-15.1). Women with early-stage disease were also more likely than women with locally advanced disease to complete treatment (OR 2.2, 95% CI 1.1-4.4). Among 100 women with available information about ubudehe (Rwandan social categorization used as a proxy for socioeconomic status), rates of treatment completion were higher for women who were eligible for social support (ie: transportation support or insurance subsidy) than women who were not (74% v. 63%), although this difference was not statistically significant (p= 0.51). Conclusions: Significant barriers exist for breast cancer patients receiving treatment in this low resource setting; nevertheless, over half of the patients completed therapy. Interventions are needed to facilitate care for women with long travel times and locally advanced disease to reduce disparities in outcomes for this population of patients. Further research is needed to determine the role of social support in treatment completion.
Multimorbidity in women with breast cancer may delay presentation, affect treatment decisions and outcomes. We described the multimorbidity profile of women with breast cancer, its determinants, associations with stage at diagnosis and treatments received. We collected self‐reported data on five chronic conditions (hypertension, diabetes, cerebrovascular diseases, asthma/chronic obstructive pulmonary disease, tuberculosis), determined obesity using body mass index (BMI) and tested HIV status, in women newly diagnosed with breast cancer between January 2016 and April 2018 in five public hospitals in South Africa. We identified determinants of ≥2 of the seven above‐mentioned conditions (defined as multimorbidity), multimorbidity itself with stage at diagnosis (advanced [III–IV] vs . early [0–II]) and multimorbidity with treatment modalities received. Among 2,281 women, 1,001 (44%) presented with multimorbidity. Obesity (52.8%), hypertension (41.3%), HIV (22.0%) and diabetes (13.7%) were the chronic conditions that occurred most frequently. Multimorbidity was more common with older age (OR = 1.02; 95% CI 1.01–1.03) and higher household socioeconomic status (HSES) (OR = 1.06; 95% CI 1.00–1.13). Multimorbidity was not associated with advanced‐stage breast cancer at diagnosis, but for self‐reported hypertension there was less likelihood of being diagnosed with advanced‐stage disease in the adjusted model (OR 0.80; 95% CI 0.64–0.98). Multimorbidity was associated with first treatment received in those with early‐stage disease, p = 0.003. The prevalence of multimorbidity is high among patients with breast cancer. Our findings suggest that multimorbidity had a significant impact on treatment received in those with early‐stage disease. There is need to understand the impact of multimorbidity on breast cancer outcomes.
Abstract 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.
We aimed to evaluate for associations between HIV status, psychosocial factors, and adjuvant endocrine therapy (AET) adherence in South African (SA) women with estrogen receptor positive (ER+) breast cancer (BC).
Abstract Background In the U.S., neoadjuvant chemotherapy (NAC) for nonmetastatic breast cancer (BC) is used with extensive disease and aggressive molecular subtypes. Little is known about the influence of demographic characteristics, clinical factors, and resource constraints on NAC use in Africa. Materials and Methods We studied NAC use in a cohort of women with stage I–III BC enrolled in the South African Breast Cancer and HIV Outcomes study at five hospitals. We analyzed associations between NAC receipt and sociodemographic and clinical factors, and we developed Cox regression models for predictors of time to first treatment with NAC versus surgery. Results Of 810 patients, 505 (62.3%) received NAC. Multivariate analysis found associations between NAC use and black race (odds ratio [OR] 0.49; 95% confidence limit [CI], 0.25–0.96), younger age (OR 0.95; 95% CI, 0.92–0.97 for each year), T-stage (T4 versus T1: OR 136.29; 95% CI, 41.80–444.44), N-stage (N2 versus N0: OR 35.64; 95% CI, 16.56–76.73), and subtype (triple-negative versus luminal A: OR 5.16; 95% CI, 1.88–14.12). Sites differed in NAC use (Site D versus Site A: OR 5.73; 95% CI, 2.72–12.08; Site B versus Site A: OR 0.37; 95% CI, 0.16–0.86) and time to first treatment: Site A, 50 days to NAC versus 30 days to primary surgery (hazard ratio [HR] 1.84; 95% CI, 1.25–2.71); Site D, 101 days to NAC versus 126 days to primary surgery (HR 0.49; 95% CI, 0.27–0.89). Conclusion NAC use for BC at these South African hospitals was associated with both tumor characteristics and heterogenous resource constraints.
High-quality histopathology reporting forms the basis for treatment decisions. The quality indicator for pathology reports from the European Society of Breast Cancer Specialists was applied to a cohort from four South African breast units.The study included 1,850 patients with invasive breast cancer and evaluated 1,850 core biopsies and 1,158 surgical specimen reports with cross-center comparisons. A core biopsy report required histologic type; tumor grade; and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status, with a confirmatory test for equivocal HER2 results. Ki-67 was regarded as optional. Pathologic stage, tumor size, lymphovascular invasion, and distance to nearest invasive margin were mandatory for surgical specimens. Specimen turnaround time (TAT) was added as a locally relevant indicator.Seventy-five percent of core biopsy and 74.3% of surgical specimen reports were complete but showed large variability across study sites. The most common reason for an incomplete core biopsy report was missing tumor grade (17.9%). Half of the equivocal HER2 results lacked confirmatory testing (50.6%). Ki-67 was reported in 89.3%. For surgical specimens, the closest surgical margin was reported in 78.1% and lymphovascular invasion in 84.8% of patients. Mean TAT was 11.9 days (standard deviation [SD], 10.8 days) for core biopsies and 16.1 days (SD, 11.3) for surgical specimens.Histopathology reporting is at a high level but can be improved, especially for tumor grade, HER2, and Ki-67, as is reporting of margins and lymphovascular invasion. A South African pathology consensus will reduce variability among laboratories. Routine use of standardized data sheets with synoptic reports and ongoing audits will improve completeness of reports over time.
Quality indicators (QIs) for breast cancer care have been developed and applied in high-income countries and contributed to improved quality of care and patient outcomes over time.A modified Delphi process was used to derive expert consensus. Potential QIs were rated by a panel of 17 breast cancer experts from various subspecialties and across South African provinces. Each QI was rated according to importance to measure, scientific acceptability and feasibility. Scoring ranged from 1 (no agreement) to 5 (strong agreement). Inclusion thresholds were set a priori at mean ratings ≥4 with a coefficient variation of ≥25%. Levels of evidence were determined for each indicator.The literature review identified 790 potential QIs. After categorisation and removal of duplicates, 52 remained for panel review. There was strong consensus for 47 which were merged to 30 QIs by exclusion of similar indicators and indicator grouping. The final set included eight QIs with level I or II evidence and two QIs with level III evidence which were deemed "mandatory" due to clinical priority and impact on care. The remaining QIs with lower-level evidence were grouped as eight "recommended" QIs (regarded as standard of care) and twelve "optional" QIs (not regarded as standard of care).A regional set of QIs was developed to facilitate standardised treatment and auditing of surgical care for breast cancer patients in South Africa. Routine monitoring of the ten mandatory QIs, which were selected to have the most substantial impact on patient outcome, is proposed.
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