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PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.
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Anastrozol , Androstadienos , Neoplasias da Mama , Pós-Menopausa , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Anastrozol/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Receptores de Progesterona/metabolismo , Receptores de Progesterona/análise , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Androstadienos/uso terapêutico , Androstadienos/administração & dosagem , Pessoa de Meia-Idade , Idoso , Canadá , Quimioterapia Adjuvante , Intervalo Livre de DoençaRESUMO
PURPOSE: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. PATIENTS AND METHODS: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). RESULTS: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. CONCLUSIONS: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.
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Inibidores da Aromatase , Neoplasias da Mama , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Anastrozol/uso terapêutico , Anastrozol/efeitos adversos , Anastrozol/administração & dosagem , Estudos de Coortes , Pós-Menopausa , Idoso de 80 Anos ou mais , Medidas de Resultados Relatados pelo Paciente , Aromatase/genéticaRESUMO
Third-generation aromatase inhibitors (AI) are the standard treatment for patients with hormone receptor positive (HR+) breast cancer. While effective, AI can lead to severe adverse events, including AI-induced musculoskeletal syndrome (AIMSS). Genetic predictors of AIMSS have the potential to personalize AI treatment and improve outcomes. We attempted to replicate results from a previous genome-wide association study that found a lower risk of AIMSS in patients carrying PPP1R14C rs912571 and a higher risk in patients carrying CCDC148 rs79048288. AIMSS data were collected prospectively from patients with HR+ breast cancer prior to starting and after 3 and 6 months of adjuvant AI via the Patient-Reported Outcome Measurement Information System and Functional Assessment of Cancer Therapy-Endocrine Symptom. Germline genotypes for PPP1R14C rs912571 and CCDC148 rs79048288 were tested for a similar association with AIMSS as previously reported via $2 tests. Of the 143 patients with AIMSS and genetics data were included in the analysis. There was no association identified between PPP1R14C rs912571 and AIMSS risk ( P â >â 0.05). Patients carrying CCDC148 rs79048288 variant alleles had lower AIMSS incidence in a secondary analysis ( P â =â 0.04); however, this was in the opposite direction of the previous finding. The study did not replicate previously reported associations with AIMSS risk for genetic variants in PPP1R14C and CCDC148 and AIMSS risk. Further research is needed to discover and validate genetic predictors of AIMSS that can be used to personalize treatment in patients with HR+ breast cancer.
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Inibidores da Aromatase , Neoplasias da Mama , Peptídeos e Proteínas de Sinalização Intracelular , Doenças Musculoesqueléticas , Variantes Farmacogenômicos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/induzido quimicamente , Polimorfismo de Nucleotídeo Único/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Ipilimumab , Nivolumabe , Piridinas , Receptor ErbB-2 , Humanos , Feminino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Adulto , Receptor ErbB-2/metabolismo , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Idoso , Ipilimumab/uso terapêutico , Ipilimumab/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Intervalo Livre de ProgressãoRESUMO
Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34-70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = - 0.69, p = 0.018, and Cohen's d = - 1.104), anxiety (ρ = - 0.61, p = .046, d = - 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.
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Sobreviventes de Câncer , Neoplasias , Humanos , Fosfocreatina/metabolismo , Saúde Mental , Neoplasias/metabolismo , Músculo Esquelético/metabolismo , Estresse OxidativoRESUMO
PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.
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Inibidores da Aromatase , Neoplasias da Mama , Feminino , Humanos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/induzido quimicamente , Letrozol/uso terapêutico , Polimedicação , Estudos Prospectivos , Adesão à MedicaçãoRESUMO
Objectives: Early discontinuation is common among breast cancer patients taking aromatase inhibitors (AIs). Although several predictors have been identified, it is unclear how to simultaneously consider multiple risk factors for an individual. We sought to develop a tool for prediction of AI discontinuation and to explore how predictive value of risk factors changes with time. Materials and Methods: Survival machine learning was used to predict time-to-discontinuation of AIs in 181 women who enrolled in a prospective cohort. Models were evaluated via time-dependent area under the curve (AUC), c-index, and integrated Brier score. Feature importance was analysis was conducted via Shapley Additive Explanations (SHAP) and time-dependence of their predictive value was analyzed by time-dependent AUC. Personalized survival curves were constructed for risk communication. Results: The best-performing model incorporated genetic risk factors and changes in patient-reported outcomes, achieving mean time-dependent AUC of 0.66, and AUC of 0.72 and 0.67 at 6- and 12-month cutoffs, respectively. The most significant features included variants in ESR1 and emergent symptoms. Predictive value of genetic risk factors was highest in the first year of treatment. Decrease in physical function was the strongest independent predictor at follow-up. Discussion and Conclusion: Incorporation of genomic and 3-month follow-up data improved the ability of the models to identify the individuals at risk of AI discontinuation. Genetic risk factors were particularly important for predicting early discontinuers. This study provides insight into the complex nature of AI discontinuation and highlights the importance of incorporating genetic risk factors and emergent symptoms into prediction models.
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BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.
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Neoplasias Inflamatórias Mamárias , Nitrilas , Paclitaxel , Pirazóis , Pirimidinas , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/patologia , Interleucina-6 , Terapia Neoadjuvante , Nitrilas/uso terapêutico , Paclitaxel/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
This study aims to examine the feasibility of DNA methylation age as a biomarker for symptoms and resilience in cancer survivors with multiple chronic conditions (MCCs). We included ten participants from our parent study, an ongoing randomized control trial study. Participants' symptoms and resilience were assessed, and peripheral blood was collected. DNA methylation age calculation was performed using DNAge® analysis. Data were analyzed using Spearman's correlation analysis and the Mann-Whitney U test. Participants in the intervention group tended to have a decrease in DNA methylation age and age acceleration after completing an exercise program (mean difference = -0.83 ± 1.26). The change in DNA methylation age was significantly correlated with the change in resilience score (r = -0.897, p = 0.015). The preliminary results suggest that DNA methylation age can be a potential biomarker for improving resilience in cancer survivors with multiple chronic conditions. This finding is limited by the small sample size, and a larger study is needed.
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PURPOSE: Treatment-associated symptoms drive early discontinuation of adjuvant endocrine therapy (ET) for breast cancer. We hypothesized that symptom monitoring with electronic patient-reported outcomes (ePROs) during adjuvant ET will enhance symptom detection, symptom management, and persistence. METHODS: Eligible patients were initiating ET for stage 0-III breast cancer. Participants completed ePRO surveys via smartphone at baseline and 1, 3, 6, and 12 months. Measures included Patient-Reported Outcomes Measurement Information System Anxiety, Depression, Fatigue, and Vaginal Discomfort; plus Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items assessing joint pain, hot flashes, vaginal dryness, concentration problems, and memory problems. Scores surpassing prespecified thresholds triggered alerts, and recommended symptom management pathways were provided to clinicians. The primary objective was to evaluate feasibility, assessed by survey completion rates, with targets of >65% for the baseline survey and ≥1 follow-up survey during the first 6 months. Secondary objectives included 12-month ET discontinuation rate (target: ≤15%), describing symptoms and evaluating pathway implementation. RESULTS: Among 250 participants, 73.2% completed the baseline survey and 69.6% completed ≥1 follow-up survey during the first 6 months. Thirty-one percent of participants had ≥1 symptom alert at baseline and 74% had ≥1 symptom alert during follow-up. The proportions of participants for whom pathway-concordant symptom management was documented at each time point ranged from 12.8% to 36.6%. Twenty-eight participants (11.2%) discontinued ET by 12 months. CONCLUSION: Symptom monitoring with ePROs during adjuvant ET is feasible. Despite infrequent documentation of pathway-concordant symptom management after symptom alerts, ePROs were associated with favorable short-term ET persistence.
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Neoplasias da Mama , Aplicativos Móveis , Feminino , Humanos , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Estudos de Viabilidade , Inquéritos e Questionários , Medidas de Resultados Relatados pelo PacienteRESUMO
Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SULmax) on 18F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that 18F-FDG PET/CT SULmax parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. 18F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between 18F-FDG PET/CT (≥40% decline in SULmax between baseline and C1D15, or C1D15 SULmax ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SULmax of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SULmax decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SULmax of 3 or less on 18F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Resultado do Tratamento , Receptor ErbB-2/metabolismo , Trastuzumab , Tomografia por Emissão de Pósitrons , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.
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Neoplasias Ovarianas , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Proteína BRCA1/genética , Platina , Proteína BRCA2/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Instabilidade Genômica , Recombinação HomólogaRESUMO
Purpose: To report outcomes on a subset of patients with triple negative breast cancer (TNBC) treated on prospective trials with post-lumpectomy partial breast irradiation and concurrent chemotherapy (PBICC) and compare them to a retrospectively assessed similar cohort treated with whole breast irradiation after adjuvant chemotherapy (WBIaC). Methods and materials: Women with T1-2, N0-1 invasive breast cancer with ≥ 2mm lumpectomy margins were offered therapy on one of two PBICC trials. PBI consisted of 40.5 Gy in 15 daily 2.7 Gy fractions delivered concurrently with the first 2 cycles of adjuvant chemotherapy. The comparison cohort received WBI to a median dose of 60.7 Gy, (including boost, range 42.5 - 66 Gy), after completion of non-concurrent, adjuvant chemotherapy. We evaluated disease-free survival (DFS), and local/loco-regional/distant recurrence-free survival (RFS). We compared survival rates using Kaplan-Meier curves and log-rank test of statistical significance. Results: Nineteen patients with TNBC were treated with PBICC on prospective protocol, and 49 received WBIaC. At a median follow-up of 35.5 months (range 4.8-71.9), we observed no deaths in the PBICC cohort and 2 deaths in the WBIaC cohort (one from disease recurrence). With a median time of 23.4 (range 4.8 to 47) months, there were 7 recurrences (1 nodal, 4 local, 4 distant), all in the WBIaC group. At 5 years, there was a trend towards increased local RFS (100% vs. 85.4%, p=0.17) and loco-regional RFS (100% vs. 83.5, p=0.13) favoring the PBICC cohort. There was no significant difference in distant RFS between the two groups (100% vs. 94.4%, p=0.36). Five-year DFS was 100% with PBICC vs.78.9% (95% CI: 63.2 to 94.6%, p=0.08) with WBIaC. Conclusion: This study suggests that PBICC may offer similar and possibly better outcomes in patients with TNBC compared to a retrospective cohort treated with WBIaC. This observation is hypothesis-generating for prospective trials.
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PURPOSE: Weight gain after breast cancer poses health risks. We aimed to identify factors associated with weight gain during adjuvant endocrine therapy (AET). METHODS: Women initiating AET enrolled in a prospective cohort. Participants completed FACT-ES plus PROMIS pain interference, depression, anxiety, fatigue, sleep disturbance and physical function measures at baseline, 3, 6, 12, 24, 36, 48 and 60 months. Treatment-emergent symptoms were defined as changes in scores in the direction indicative of worsening symptoms that exceeded the minimal important difference at 3 and/or 6 months compared to baseline. We used logistic regression to evaluate associations of clinicodemographic features and treatment-emergent symptoms with clinically significant weight gain over 60 months (defined as ≥ 5% compared to baseline) in pre- and post-menopausal participants. RESULTS: Of 309 participants, 99 (32%) were pre-menopausal. The 60 months cumulative incidence of clinically significant weight gain was greater in pre- than post-menopausal participants (67% vs 43%, p < 0.001). Among pre-menopausal participants, treatment-emergent pain interference (OR 2.49), aromatase inhibitor receipt (OR 2.8), mastectomy, (OR 2.06) and White race (OR 7.13) were associated with weight gain. Among post-menopausal participants, treatment-emergent endocrine symptoms (OR 2.86), higher stage (OR 2.25) and White race (OR 2.29) were associated with weight gain while treatment-emergent physical function decline (OR 0.30) was associated with lower likelihood of weight gain. CONCLUSIONS: Weight gain during AET is common, especially for pre-menopausal women. Clinicodemographic features and early treatment-emergent symptoms may identify at risk individuals. IMPLICATIONS FOR CANCER SURVIVORS: Patients at risk for weight gain can be identified early during AET. GOV IDENTIFIER: NCT01937052, registered September 3, 2013.
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Purpose: To examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT). Patients and Methods: We identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. Results: Of 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 -4 (range: 7.9 × 10 -7 to 4.9 × 10 -1 ). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12. Conclusion: NAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.
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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS.[Media: see text].
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Neoplasias da Mama , Adulto , Feminino , Humanos , Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Seguimentos , Pré-Menopausa , Tamoxifeno/uso terapêuticoRESUMO
Applications based on artificial intelligence (AI) and deep learning (DL) are rapidly being developed to assist in the detection and characterization of lesions on medical images. In this study, we developed and examined an image-processing workflow that incorporates both traditional image processing with AI technology and utilizes a standards-based approach for disease identification and quantitation to segment and classify tissue within a whole-body [18F]FDG PET/CT study. Methods: One hundred thirty baseline PET/CT studies from two multi-institutional preoperative clinical trials in early-stage breast cancer were semi-automatically segmented using techniques based on PERCIST v1.0 thresholds and the individual segmentations classified as to tissue type by an experienced nuclear medicine physician. These classifications were then used to train a convolutional neural network (CNN) to automatically accomplish the same tasks. Results: Our CNN-based workflow demonstrated Sensitivity at detecting disease (either primary lesion or lymphadenopathy) of 0.96 (95% CI [0.9, 1.0], 99% CI [0.87,1.00]), Specificity of 1.00 (95% CI [1.0,1.0], 99% CI [1.0,1.0]), DICE score of 0.94 (95% CI [0.89, 0.99], 99% CI [0.86, 1.00]), and Jaccard score of 0.89 (95% CI [0.80, 0.98], 99% CI [0.74, 1.00]). Conclusion: This pilot work has demonstrated the ability of AI-based workflow using DL-CNNs to specifically identify breast cancer tissue as determined by [18F]FDG avidity in a PET/CT study. The high sensitivity and specificity of the network supports the idea that AI can be trained to recognize specific tissue signatures, both normal and disease, in molecular imaging studies using radiopharmaceuticals. Future work will explore the applicability of these techniques to other disease types and alternative radiotracers, as well as explore the accuracy of fully automated and quantitative detection and response assessment.
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BACKGROUND: Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18-70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138. FINDINGS: Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 -39% [95% CI -46 to -31] vs placebo -26% [-33 to -18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events. INTERPRETATION: Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy. FUNDING: QUE Oncology.
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Inibidores da Aromatase , Neoplasias da Mama , Humanos , Feminino , Masculino , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/efeitos adversos , Método Duplo-Cego , Resultado do Tratamento , Fogachos/induzido quimicamente , Fogachos/tratamento farmacológicoRESUMO
PURPOSE: Sexual function problems are common but under-reported among women receiving adjuvant endocrine therapy for breast cancer. Worsening scores on patient-reported outcomes (PROs) may identify those at risk for sexual function problems during treatment. We performed a secondary analysis of prospectively collected PROs in women receiving adjuvant endocrine therapy to identify factors associated with worsening sexual function. METHODS: Women with stage 0-III breast cancer initiating adjuvant endocrine therapy participating in a prospective cohort completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Sexual function was evaluated by the MOS-SP measure. Other measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance and the Endocrine Symptom Subscale of the FACT-ES. We evaluated associations between score worsening of at least the minimal important difference (MID) in PROMIS T-scores (4 points) and FACT-ES scores (5 points) with score worsening of at least the MID in MOS-SP scores (8 points) using logistic regression. RESULTS: Among 300 participants, 45.7% experienced ≥ 8-point worsening of MOS-SP score at any time point compared to baseline. Worsening endocrine symptoms (OR 1.34, 95% CI 1.22-1.49, p < 0.001), worsening physical function (OR 1.09, 95% CI 1.00-1.18, p = 0.06), and prior mastectomy (OR 1.45, 95% CI 0.94-2.23, p = 0.09) were associated with MOS-SP score worsening by at least the MID. CONCLUSION: Worsening endocrine symptoms and physical function identified on PROs are associated with worsening sexual function during adjuvant endocrine therapy. Routine assessment of these domains with PROs may identify women at risk for sexual function problems. TRIAL REGISTRATION NUMBER: NCT01937052; Date of Registration: 09/09/2013.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/efeitos adversos , Mastectomia , Estudos Prospectivos , Qualidade de VidaRESUMO
Current molecular liquid biopsy assays to detect recurrence or monitor response to treatment require sophisticated technology, highly trained personnel, and a turnaround time of weeks. We describe the development and technical validation of an automated Liquid Biopsy for Breast Cancer Methylation (LBx-BCM) prototype, a DNA methylation detection cartridge assay that is simple to perform and quantitatively detects nine methylated markers within 4.5 h. LBx-BCM demonstrated high interassay reproducibility when analyzing exogenous methylated DNA (75-300 DNA copies) spiked into plasma (Coefficient of Variation, CV = 7.1 - 10.9%) and serum (CV = 19.1 - 36.1%). It also demonstrated high interuser reproducibility (Spearman r = 0.887, P < 0.0001) when samples of metastatic breast cancer (MBC, N = 11) and normal control (N = 4) were evaluated independently by two users. Analyses of interplatform reproducibility indicated very high concordance between LBx-BCM and the reference assay, cMethDNA, among 66 paired plasma samples (MBC N = 40, controls N = 26; Spearman r = 0.891; 95% CI = 0.825 - 0.933, P< 0.0001). LBx-BCM achieved a ROC AUC = 0.909 (95% CI = 0.836 - 0.982), 83% sensitivity and 92% specificity; cMethDNA achieved a ROC AUC = 0.896 (95% CI = 0.817 - 0.974), 83% sensitivity and 92% specificity in test set samples. The automated LBx-BCM cartridge prototype is fast, with performance levels equivalent to the highly sensitive, manual cMethDNA method. Future prospective clinical studies will evaluate LBx-BCM detection sensitivity and its ability to monitor therapeutic response during treatment for advanced breast cancer.