Search

Purpose: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients. Methods: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole ( n = 241) or exemestane ( n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. Results: The ranges of baseline estrogen concentrations were

Objectives Optimal conditions for blood collection for circulating tumor DNA (ctDNA) are still being developed. Although both Streck and EDTA tubes are commonly used, their ability to stabilize ctDNA as a function of time and temperature post-collection has not been thoroughly studied. Additionally, the potential utility of CellSave tubes (commonly used for circulating tumor cell) for ctDNA measurements has not been studied. Design and methods Blood was collected into Streck, EDTA, and CellSave tubes from ten patients with metastatic breast cancer enrolled in the MI-ONCOSEQ tumor sequencing program at the University of Michigan and kept either on ice or at room temperature until plasma isolation. Plasma was processed after 2, 6, and 48 h post-collection. We used droplet digital PCR (ddPCR) to quantify plasma ctDNA and wild-type DNA for six patients who had tumor tissue mutations represented in commercially available ddPCR assays. Results ctDNA abundance was similar and stable for up to 6 h in all tube types, and there was no effect of storage temperature on the yield for Streck and EDTA tubes. After 48 h, however, one out of four patients with detectable ctDNA showed a ~ 50% decline in ctDNA in the EDTA tube, and three out of six patients showed a 2–3-fold increase in wild-type DNA in the EDTA tube. Conclusions Streck, EDTA, and CellSave tubes showed similar performance in preserving ctDNA for up to 6 h before plasma isolation. Streck and CellSave tubes more consistently stabilized ctDNA and wild-type DNA at 48 h than EDTA tubes. [ABSTRACT FROM AUTHOR]

Fulvestrant is a dose dependent selective estrogen receptor (ER) down-regulator (SERD) used in ER-positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch ® system. Clinical data are limited to a subset of patients with ER-positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10). CTCs were enumerated and phenotyped for ER and B-cell lymphoma (BCL2) using the CellSearch ® CXC kit. In preclinical modeling, tamoxifen and AIs resulted in stabilized ER expression, whereas fulvestrant eliminated it. Five of seven patients progressing on fulvestrant had ≥5CTC/7.5 ml WB. Two of these five, treated with 500 mg/month fulvestrant, had no detectable CTC-expression of ER and BCL2 (an ER regulated gene). Three patients had heterogeneous CTC-ER and BCL2 expression indicating incomplete degradation of the ER target by fulvestrant. Two of these patients received 250 mg/month whereas the third patient received 500 mg/month fulvestrant. Her cancer harbored a mutation (Y537S) in the estrogen receptor alpha gene ( ESR1 ). All seven ER positive patients progressing on AIs had heterogeneous CTC-ER expression. These results suggest heterogeneous mechanisms of resistance to fulvestrant, including insufficient dosage, ESR1 mutation, or conversion to dependence on non-ER pathways. CTC enumeration, phenotyping, and genotyping might identify patients who would benefit from fulvestrant dose escalation versus switching to alternative therapies. [ABSTRACT FROM AUTHOR]

Background Cancer pharmacogenetic studies use archival tumor samples as a DNA source when germline DNA is unavailable. Genotyping DNA from formalin-fixed paraffin embedded tumors (FFPE-T) may be inaccurate due to FFPE storage, genetic aberrations, and/or insufficient DNA extraction. Our objective was to assess the extent and source of genotyping inaccuracy from FFPE-T DNA and demonstrate analytical validity of FFPE-T genotyping of candidate single nucleotide polymorphisms (SNPs) for pharmacogenetic analyses. Methods Cancer pharmacogenetics SNPs were genotyped by Sequenom MassARRAYs in DNA harvested from matched FFPE-T, FFPE lymph node (FFPE-LN), and whole blood leukocyte samples obtained from breast cancer patients. No- and discordant-call rates were calculated for each tissue type and SNP. Analytical validity was defined as any SNP with <5% discordance between FFPE-T and blood and <10% discordance plus no-calls. Results Matched samples from 114 patients were genotyped for 247 SNPs. No-call rate in FFPE-T was greater than FFPE-LN and blood (4.3% vs. 3.0% vs. 0.5%, p < 0.001). Discordant-call rate between FFPE-T and blood was very low, but greater than that between FFPE-LN and blood (1.1% vs. 0.3%, p < 0.001). Samples with heterozygous genotypes were more likely to be no- or discordantly-called in either tissue (p < 0.001). Analytical validity of FFPE-T genotyping was demonstrated for 218 (88%) SNPs. Conclusions No- and discordant-call rates were below concerning thresholds, confirming that most SNPs can be accurately genotyped from FFPE-T on our Sequenom platform. FFPE-T is a viable DNA source for prospective–retrospective pharmacogenetic analyses of clinical trial cohorts. [ABSTRACT FROM AUTHOR]

Background. Reproductive-aged women frequently receive both chemotherapy and endocrine therapy as part of their treatment regimen for early stage hormone receptor-positive breastcancer.Chemotherapyresults in transient orpermanent ovarian failure in the majority of women. The difficulty in determining which patients will recover ovarian function has implications for adjuvant endocrine therapy decision making. We hypothesized that pretreatment serum anti-Mülerian hormone (AMH) and inhibin B concentrations would predict for ovarian function following chemotherapy. Methods. Pre- and perimenopausal women aged 25–50 years with newly diagnosed breast cancer were enrolled. Subjects underwentphlebotomy for assessment of serum AMH,inhibin B,follicle-stimulating hormone, and estradiol prior to chemotherapy and 1month and 1 year following completion of treatment. Associations among hormone concentrations, clinical factors, and biochemically assessed ovarian function were assessed. Results. Twenty-seven subjects were evaluable for the primary endpoint. Median age was 41.Twenty subjects (74.1%) experienced recovery of ovarian function within 18 months. Of the 26 evaluable subjects assessed prior to chemotherapy, 19 (73.1%) had detectable serum concentrations of AMH. The positive predictive value of a detectable baseline serum AMH concentration for recovery of ovarian function was 94.7%, and the negative predictive value was 85.7%. On univariate analysis, younger age and detectable serum AMH concentration at chemotherapy initiationwere predictive of increased likelihood of recovery of ovarian function. Conclusion. Prechemotherapy assessment of serum AMH may be useful for predicting postchemotherapy ovarian function. This finding has implications for decision making about adjuvant endocrine therapy in premenopausal women treated with chemotherapy. The Oncologist 2014; 19:68–74 [ABSTRACT FROM AUTHOR]

La Sra. B, mujer de 45 años de edad, casada, premenopáusica, fue diagnosticada de trastorno depresivo mayor hace 10 años y posteriormente tratada con éxito durante 12 meses con fluoxetina (20 mg/día), sin efectos secundarios significativos. Permaneció sin síntomas depresivos durante los siguientes 8-9 años. Hace 1 año se le diagnosticó un cáncer de mama invasivo con receptor de estrógeno positivo y se sometió a tratamiento quirúrgico, seguido de quimioterapia y posterior radioterapia. La Sra. B ha sido tratada con tamoxifeno (un modulador selectivo de los receptores de estrógenos) durante los últimos 6 meses, para reducir la probabilidad de recurrencia del cáncer de mama. Ha tolerado el tamoxifeno relativamente bien, excepto por la aparición de sofocos moderadamente molestos, para los que no ha recibido tratamiento farmacológico. Sin embargo, hace poco tiempo, desarrolló síntomas depresivos recurrentes y solicitó tratamiento a su psiquiatra. ¿Cuáles son los agentes farmacológicos eficaces contra la depresión y los sofocos en mujeres con cáncer de mama? ¿Podría alguno de dichos fármacos alterar la eficacia del tamoxifeno o aumentar su toxicidad a través de una interacción medicamentosa? [ABSTRACT FROM AUTHOR]

The article focuses on studies making the use of gene-expression profiling to recommend adjuvant chemotherapy for breast cancer. One study evaluated breast cancer survivors, treated with cyclophosphamide, methotrexate, and fluorouracil (CMF). Clinicians use multiple methods to determine prognosis. It is being observed that gene expression profiling using DNA and RT-PCR methods is becoming widespread with advances in the fields of technology and bioinformatics.

Although breast cancer incidence continues to increase, mortality has been decreasing, principally as a result of earlier detection and improvements in adjuvant systemic therapy. Nonetheless, because antineoplastic agents are associated with substantial morbidity and occasional mortality, efforts to individualize treatment strategies are desirable. In addition to classic histopathologic diagnosis, molecular and cellular tumor markers may help in establishing prognosis or prediction of benefit. Recommendations for routine use of tumor markers in breast cancer have been conservative. Although several studies have been reported, few are of sufficiently high level of evidence to permit solid conclusions. Three key issues in tumor marker evaluation are utility, magnitude, and reliability. Poorly conceived study designs cloud the issue of how the marker might be used. Reliance on p-values rather than the size of the differences in outcome between patients who are positive and those who are negative for the factor obscures the importance. Technical issues result in poor reproducibility and interpretability of assays. Analytical issues lead to poorly defined cutoff values for marker levels. Poor patient selection leads to difficulty interpreting results because of confounders such as differences in treatment regimens. This review focuses on these issues, with an emphasis on currently accepted tumor markers. Finally, new tumor marker reporting recommendations are discussed, the adoption of which may lead to improved design and publication of tumor marker studies in the future. [ABSTRACT FROM AUTHOR]

Bladder cancer is the fifth most common cancer diagnosed in the United States. Prognosis for this disease is dependent on both tumor stage and grade. Radical cystectomy has been the standard treatment for muscle-invasive local disease; however, combined-modality approaches with the use of chemotherapy are gaining momentum with data suggesting survival improvement. Patients with metastatic disease have poor long-term survival rates despite systemic multiagent chemotherapy. A variety of agents, including newer cytotoxic drugs and biologically targeted agents, are under investigation to determine the most effective regimen. The special needs of specific patient populations, such as the elderly, those with a suboptimal performance status, and patients with medical comorbidities have gained more attention. Progress in the treatment of this disease is dependent on supporting ongoing and future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Annual or biennial breast cancer screenings are recommended for women 40 and older. Women residing in rural areas have worse breast cancer survival rates than urban women, but no study has focused on rural versus urban residence in Utah regarding breast cancer screening and mortality. Methods: Cases (n = 14,516) were women aged > 39 diagnosed with a first primary invasive breast cancer between 1998 and 2017 in Utah. Controls (n = 63,117) without a history of breast cancer were matched to cases by birth year and birth state. Mammography screening status was identified by Current Procedural Terminology (CPT) codes. Logistic regression was used to assess the odds of breast cancer diagnosis. The Cox proportional hazards model was used to assess survival outcomes for rural and urban breast cancer patients based on screening status. Results: Screening mammography usage among rural patients diagnosed with breast cancer was lower (17.7%) than urban usage (20.7%). Usage of screening mammograms resulted in higher odds of breast cancer diagnosis at localized stage rather than at a regional and distant stage. Rural breast cancer cases had a higher proportion of deaths, and a lower proportion screened, than urban breast cancer cases. Hazard ratios showed that screening mammography usage was associated with better survival among both rural (HR = 0.50, 95% CI = 0.44–0.57) and urban (HR = 0.56, 95% CI = 0.39–0.82) breast cancer cases. Conclusion: Screening mammography usage was associated with better overall survival regardless of place of residence. Removing barriers and improving information regarding breast cancer screenings are needed in both rural and urban settings in Utah to increase mammography usage, with the overall goal of increasing early detection and outcomes of breast cancer. [ABSTRACT FROM AUTHOR]

PURPOSE: Assessing risk of recurrence for nonmetastatic triple-negative breast cancer (TNBC) is a key determinant of therapeutic strategy. The best predictor of recurrence risk is failure to achieve a pathologic complete response after preoperative chemotherapy, but it imperfectly correlates with the definitive end points of relapse-free and overall survival (OS). The inability to accurately predict recurrence has led to increasingly toxic treatment regimens for patients with early-stage TNBC. Better assays for recurrence risk are needed to tailor aggressive therapy for patients who need it and avoid overtreatment and unnecessary toxicity for those at low risk. The purpose of this study was to determine if patient-derived xenograft (PDX) engraftment of newly diagnosed breast tumors can serve as an accurate predictor of recurrence and death from breast cancer. METHODS: This study was a blinded noninterventional trial comprising 80 patients with newly diagnosed, nonmetastatic, estrogen receptor (ER)-negative or ER-low breast cancer. RESULTS: PDX engraftment was strongly associated with relapse in 1 year: 8 of 18 (44.4%) patients whose tumors engrafted relapsed versus 1 of 62 (1.6%) patients whose tumors did not engraft (P <.0001). Patients whose tumors engrafted had a hazard ratio (HR) for relapse of 17.5. HRs for OS and breast cancer-specific survival in PDX+ patients were 21.1 and 39.5, respectively. CONCLUSION: We report that the ability of a tumor to engraft as a PDX predicts early recurrence by serving as a functional readout of aggressiveness and prospectively identifies the most devastating tumors. This provides new opportunity to develop surrogate assays, such as biomarkers of engraftment, which will extend the clinical feasibility of this finding. [ABSTRACT FROM AUTHOR]

The article reviews the article "CYP2D6 testing in breast cancer: Ready for prime time?" by N.M. Kuderer and J. Peppercorn, which appeared in the periodical "Oncology" in 2009.

Objective: To evaluate the validity of the Utah statewide All‐Payer Claims Database (APCD), we compared breast cancer‐specific treatments and dosages with gold‐standard abstraction of medical records. Study Design: In this pilot study, breast cancer treatments were abstracted by a certified tumor registrar at the Utah Cancer Registry (UCR) for patients diagnosed in 2013 with breast cancer. The abstraction of medical records was the gold standard for comparison with treatments identified in the APCD. The reliability and agreement between the treatment identified in the APCD and abstraction data were measured with sensitivity and specificity. Dose consistency was measured with the intraclass correlation coefficients (ICC). Results: Compared with the 186 abstractions, the sensitivity of the APCD to identify chemotherapy agents was high: 89% for any agent, 91% for carboplatin, 83% for docetaxel, 82% for doxorubicin, or 94.7% for biologic therapy. The consistency between the chemotherapy dosage identified in the claims and the abstraction varied from 63% to 76%. For radiotherapy, the sensitivity of the claims to identify the completed radiotherapy regimen was 66%. The ICC between radiotherapy doses identified in the claims and the abstraction was 54% (95% confidence interval [CI], 48%, 67%). Conclusions: Employing these novel methods, the claims were highly reliable in identifying cancer treatment agents overall, namely carboplatin, docetaxel, and trastuzumab. The claims were of moderate utility in capturing the treatment dose information. In addition to the APCD, the use of multiple data sources improved the completeness of cancer treatment information. [ABSTRACT FROM AUTHOR]

Background: Talazoparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the US for HER2-negative germline BRCA1/2-mutated (gBRCA1/2mut) locally advanced/metastatic breast cancer. Approval was based on results from the Phase 3 EMBRACA trial comparing efficacy and safety of talazoparib (1 mg/day) to physician's choice of therapy ([PCT]; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative gBRCA1/2mut locally advanced/ metastatic breast cancer. Objectives: The purpose of this analysis was to describe efficacy and safety outcomes of talazoparib vs PCT in US patients included in the pivotal EMBRACA study. Methods: Clinical findings from US patients enrolled in EMBRACA were analyzed. Patient characteristics, progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and safety/adverse events (AEs) were among the parameters assessed. Results: Of 431 randomized patients, 156 patients (36%) were from the US (talazoparib: 99 patients; PCT: 57 patients). Patient characteristics were balanced, although a higher percentage in the talazoparib arm had more poor prognostic features (e.g. triple-negative breast cancer, disease-free interval <12 months, and more disease sites). A total of 53 patients (53.5%) had hormone receptor (HR)+ breast cancer in the talazoparib arm and 37 patients (64.9%) had HR+ breast cancer in the PCT arm. Talazoparib improved PFS (median 9.0 [95% confi- dence interval (CI), 7.0-12.9] months) vs PCT (median 5.8 [95% CI, 4.2-6.7] months); hazard ratio (HR [95% CI]), 0.5 (0.3-0.7). ORR occurred in 51 patients (63.0%) receiving talazoparib and 11 patients (24.4%) receiving PCT. CBR was 68.7% (95% CI, 58.6-77.6) for talazoparib and 33.3% (95% CI, 21.4-47.1) for PCT; odds ratio (95% CI), 4.7 (2.2-10.6). Median duration of response was 5.0 months and 3.1 months for talazoparib and PCT, respectively. The most common AEs in the talazoparib arm included anemia, neutropenia, thrombocytopenia, fatigue, nausea, alopecia, and headache; hematologic grade 3/4 AEs occurred more often than nonhematologic AEs. Six out of 99 (6.1%) patients in the talazoparib arm and 6/43 (14.0%) patients in the PCT arm discontinued treatment. Conclusions: In US patients with HER2-negative gBRCA1/2mut locally advanced/metastatic breast cancer, talazoparib demonstrated significant improvements in outcomes vs PCT with a manageable safety profile. Note: © 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved. Clinical trial identification: NCT01945775 Funding: This study was sponsored by Medivation, which was acquired by Pfizer in September 2016. [ABSTRACT FROM AUTHOR]

Purpose: Few studies have specifically targeted symptom management interventions for adolescent and young adult (AYA) cancer survivors. A greater understanding of AYA cancer survivors' experiences with cancer treatment-related symptoms would help develop age-appropriate oncology symptom management interventions. The purpose of this qualitative analysis was to explore AYA cancer survivors' experience with cancer treatment-related symptoms. Methods: Nineteen post-treatment AYA cancer survivors (18–39 years old) who self-reported moderate–severe cancer treatment-related symptom severity participated in video conferencing or telephone interviews. The questions in the interview guide queried participants to share their experience with cancer treatment-related symptoms. Inductive content analysis was used to identify themes from the interviews. Results: The themes that emerged from the interviews included (1) cancer treatment-related symptoms negatively affected AYA cancer survivors' quality of life (e.g., symptoms served as a reminder of cancer recurrence possibility); (2) AYA cancer survivors' attitudes and feelings about communicating cancer treatment-related symptom concerns to clinicians (e.g., patient–clinician communication was bolstered when AYAs perceived that symptoms were being taken seriously); (3) AYA cancer survivors are interested in oncology symptom management clinical trials, but logistical challenges are barriers to participation; and (4) AYA cancer survivors are interested in nonpharmacological treatments for symptom management. Conclusion: Results highlight the burden of cancer treatment-related symptoms on day-to-day life among post-treatment AYA cancer survivors. Future work is needed to identify nonpharmacological symptom management interventions, strategies to improve patient–clinician communication about symptoms, and strategies to increase the visibility and accessibility of symptom management clinical trials for AYA cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. Methods: Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm. Results: In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. Conclusions: This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged. [ABSTRACT FROM AUTHOR]

Purpose: Efficient analytical methods are necessary to make reproducible inferences on single-item longitudinal ordinal patient-reported outcome (PRO) data. A thorough simulation study was performed to compare the performance of the semiparametric probabilistic index models (PIM) with a longitudinal analysis using parametric cumulative logit mixed models (CLMM). Methods: In the setting of a control and intervention arm, we compared the power of the PIM and CLMM to detect differences in PRO adverse event (AE) between these groups using several existing and novel summary scores of PROs. For each scenario, PRO data were simulated using copula multinomial models. Comparisons were also exemplified using clinical trial data. Results: On average, CLMM provided substantially greater power than the PIM to detect differences in PRO-AEs between the groups when the baseline-adjusted method was used, and a small advantage in power when using the baseline symptom as a covariate. Conclusion: Although the CLMM showed the best performance among analytical methods, it relies on assumptions difficult to verify and that might not be fulfilled in the real world, therefore our recommendation is the use of PIM models with baseline symptom as a covariate. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced alopecia (CIA) is a stigmatizing and psychologically devasting side effect of cancer treatment. Scalp cooling therapy (SCT) is the most effective method to reduce CIA, yet it is underutilized. We investigated factors that may impact scalp cooling discussion and use.Methods: We performed a retrospective review of cancer patients from 2000 to 2019 who had documentation of SCT discussion in the electronic medical record. The University of Michigan Rogel Cancer Center registry was used to identify the total number of cancer patients eligible for SCT during 2015-2019. Chi-square tests were used for outcome and patient characteristic comparisons (p < 0.05).Results: From 2000 to 2019, 194 patients had documentation of SCT discussion. Of those, 72 (43.6%) used SCT, 93 (47.9%) did not use SCT, and the remaining 29 (17.8%) had unknown SCT use. A total of 5615 cancer patients were eligible for SCT from 2015 to 2019. As compared to those who did not have documented SCT discussions, patients who had documentation of SCT discussions in that period (n = 161, 3.0%) were more likely to be female, have breast cancer, be less than 45 years old, and live in a zip code with average income > US $100,000 (all p < 0.0001). Between 2015 and 2019, 57 patients (1.02%) used SCT. On univariate analysis, patient-initiated conversation about SCT (p = 0.01) and age less than 65 (p = 0.03) were significantly associated with decision to use SCT.Conclusion: There were distinctions in the types of patients who have documented discussions about SCT. Improving patient knowledge about the availability of SCT and increasing access to this technology for all eligible cancer patients may enable more patients to achieve improved quality of life by reducing or preventing CIA. [ABSTRACT FROM AUTHOR]