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Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3, *6, and *7). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area-under-the-curve did not significantly differ between PMs (39,230 hr*ng/mL) and IM/NMs (43,546 hr*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.
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PURPOSE: Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer. METHODS: Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity. RESULTS: Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02). CONCLUSION: Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel.
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Negro ou Afro-Americano , Neoplasias da Mama , Docetaxel , Paclitaxel , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Pessoa de Meia-Idade , Estudos Prospectivos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Adulto , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Idoso , Negro ou Afro-Americano/genética , Taxoides/efeitos adversos , Taxoides/administração & dosagem , Estadiamento de Neoplasias , Mutação em Linhagem Germinativa , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/administração & dosagemRESUMO
Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.
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Nivolumabe , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Capecitabina/efeitos adversos , Nivolumabe/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Recidiva Local de Neoplasia/patologia , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.
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BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.
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Neoplasias da Mama , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Neutropenia/induzido quimicamente , Piperazinas , Piridinas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
LESSONS LEARNED: Despite U.S. Food and Drug Administration approval to reduce alopecia, data on efficacy of scalp cooling in Black patients with cancer are limited by lack of minority representation in prior clinical trials. Scalp cooling devices may have less efficacy in Black patients; additional studies are required to explore the possible causes for this, including hair texture and cap design. BACKGROUND: The Paxman scalp cooling (SC) device is U.S. Food and Drug Administration (FDA)-approved for prevention of chemotherapy-induced alopecia. Studies report 50%-80% success rates and high patient satisfaction, yet there have been no studies of SC in Black patients. We conducted a phase II feasibility study of Paxman SC with a planned enrollment of 30 Black patients receiving chemotherapy for stage I-III breast cancer. METHODS: Black patients who planned to receive at least four cycles of chemotherapy with non-anthracycline (NAC) or anthracycline (AC) regimens were eligible. Alopecia was assessed by trained oncology providers using the modified Dean scale (MDS) prior to each chemotherapy session. Distress related to alopecia was measured by the Chemotherapy Alopecia Distress Scale (CADS). RESULTS: Fifteen patients enrolled in the intervention before the study was closed early because of lack of efficacy. Median MDS and CADS increased after SC, suggesting increased hair loss (p < .001) and alopecia distress (p = .04). Only one participant was successful in preventing significant hair loss; the majority stopped SC before chemotherapy completion because of grade 3 alopecia (>50% hair loss). CONCLUSION: SC may not be efficacious in preventing alopecia in Black women. Differences in hair thickness, hair volume, and limitations of cooling cap design are possible contributing factors.
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Antineoplásicos , Neoplasias da Mama , Hipotermia Induzida , Negro ou Afro-Americano , Alopecia/induzido quimicamente , Alopecia/prevenção & controle , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Estudos Prospectivos , Qualidade de Vida , Couro CabeludoRESUMO
Richter transformation (RT) is a progression from chronic lymphocytic leukemia (CLL) to a more aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL). Due to the rarity of the disease, data regarding the molecular profile and cell of origin (COO) of RT is limited. We performed immunohistochemistry analysis for COO determination and next-generation sequencing for gene mutation analysis in 11 RT patients. Seventy-nine percent of our patients were classified as non-GCB phenotype. Of the 57 unique mutations identified, the three most commonly mutated genes were TP53, TET2, and CREBBP. Neither TET2 nor CREBBP has been previously described in RT. Our analysis provides additional information to help guide further investigation of both the diagnosis and treatment of this complex and heterogeneous disease.
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Transformação Celular Neoplásica/genética , Predisposição Genética para Doença , Variação Genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Biomarcadores Tumorais , Evolução Clonal/genética , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
INTRODUCTION: This study analyzed the cost-efficacy of intraoperative radiation therapy (IORT) compared with whole-breast irradiation (WBI) and accelerated partial-breast irradiation (APBI) for early-stage breast cancer. MATERIALS AND METHODS: Data for this analysis came from 2 phase III trials: the TARGIT (Targeted Intraoperative Radiotherapy) trial and the ELIOT (Electron Intraoperative Radiotherapy) trial. Cost analyses included a cost-minimization analysis and an incremental cost-effectiveness ratio analysis including a quality-adjusted life-year (QALY) analysis. Cost analyses were performed comparing IORT with WBI delivered using 3-dimensional conformal radiotherapy (3D-CRT), APBI 3D-CRT, APBI delivered with intensity-modulated radiotherapy (IMRT), APBI single-lumen (SL), APBI multilumen (ML), and APBI interstitial (I). RESULTS: Per 1000 patients treated, the cost savings with IORT were $3.6-$4.3 million, $1.6-$2.4 million, $3.6-$4.4 million, $7.5-$8.2 million, and $2.8-$3.6 million compared with WBI 3D-CRT, APBI IMRT, APBI SL, APBI ML, and APBI I, respectively, with a cost decrement of $1.6-$2.4 million compared with APBI 3D-CRT based on data from the TARGIT trial. The costs per QALY for WBI 3D-CRT, APBI IMRT, APBI SL, APBI ML, and APBI I compared with IORT were $47,990-$60,002; $17,335-$29,347; $49,019-$61,031; $108,162-$120,173; and $36,129-$48,141, respectively, based on data from the ELIOT trial. These results are consistent with APBI and WBI being cost-effective compared with IORT. CONCLUSION: Based on cost-minimization analyses, IORT represents a potential cost savings in the management of early-stage breast cancer. However, absolute reimbursement is misleading, because when additional medical and nonmedical costs associated with IORT are factored in, WBI and APBI represent cost-effective modalities based on cost-per-QALY analyses. They remain the standard of care.