Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221.

BACKGROUND: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor. METHODS: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet. RESULTS: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05). CONCLUSIONS: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

Prognostic Model for De Novo and Recurrent Metastatic Breast Cancer.

PURPOSE: Metastatic breast cancer (MBC) has a heterogeneous clinical course. We sought to develop a prognostic model for overall survival (OS) that incorporated contemporary tumor and clinical factors for estimating individual prognosis. METHODS: We identified patients with MBC from our institution diagnosed between 1998 and 2017. We developed OS prognostic models by Cox regression using demographic, tumor, and treatment variables. We assessed model predictive accuracy and estimated annual OS probabilities. We evaluated model discrimination and prediction calibration using an external validation data set from the National Comprehensive Cancer Network. RESULTS: We identified 10,655 patients. A model using age at diagnosis, race or ethnicity, hormone receptor and human epidermal growth factor receptor 2 subtype, de novo versus recurrent MBC categorized by metastasis-free interval, Karnofsky performance status, organ involvement, frontline biotherapy, frontline hormone therapy, and the interaction between variables significantly improved predictive accuracy (C-index, 0.731; 95% CI, 0.724 to 0.739) compared with a model with only hormone receptor and human epidermal growth factor receptor 2 status (C-index, 0.617; 95% CI, 0.609 to 0.626). The extended Cox regression model consisting of six independent models, for < 3, 3-14, 14-20, 20-33, 33-61, and ≥ 61 months, estimated up to 5 years of annual OS probabilities. The selected multifactor model had good discriminative ability but suboptimal calibration in the group of 2,334 National Comprehensive Cancer Network patients. A recalibration model that replaced the baseline survival function with the average of those from the training and validation data improved predictions across both data sets. CONCLUSION: We have generated and validated a robust prognostic OS model for MBC. This model can be used in clinical decision making and stratification in clinical trials.

Incorporation of clinical and biological factors improves prognostication and reflects contemporary clinical practice.

We developed prognostic models for breast cancer-specific survival (BCSS) that consider anatomic stage and other important determinants of prognosis and survival in breast cancer, such as age, grade, and receptor-based subtypes with the intention to demonstrate that these factors, conditional on stage, improve prediction of BCSS. A total of 20,928 patients with stage I-III invasive primary breast cancer treated at The University of Texas MD Anderson Cancer Center between 1990 and 2016, who received surgery as an initial treatment were identified to generate prognostic models by Fine-Gray competing risk regression model. Model predictive accuracy was assessed using Harrell's C-index. The Aalen-Johansen estimator and a selected Fine-Gray model were used to estimate the 5-year and 10-year BCSS probabilities. The performance of the selected model was evaluated by assessing discrimination and prediction calibration in an external validation dataset of 29,727 patients from the National Comprehensive Cancer Network (NCCN). The inclusion of age, grade, and receptor-based subtype in addition to stage significantly improved the model predictive accuracy (C-index: 0.774 (95% CI 0.755-0.794) vs. 0.692 for stage alone, p < 0.0001). Young age (<40), higher grade, and TNBC subtype were significantly associated with worse BCSS. The selected model showed good discriminative ability but poor calibration when applied to the validation data. After recalibration, the predictions showed good calibration in the training and validation data. More refined BCSS prediction is possible through a model that has been externally validated and includes clinical and biological factors.

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).

PURPOSE: Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS: Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS: There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION: Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Germline Genetic Variants in GATA3 and Breast Cancer Treatment Outcomes in SWOG S8897 Trial and the Pathways Study.

INTRODUCTION: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer. PATIENTS AND METHODS: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study. RESULTS: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue. CONCLUSIONS: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype.

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

Supplement Use and Chemotherapy-Induced Peripheral Neuropathy in a Cooperative Group Trial (S0221): The DELCaP Study.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) can interfere with daily function and quality of life, and there are no known preventive approaches. In a cohort of breast cancer patients receiving paclitaxel as part of a clinical trial (SWOG 0221), we examined the use of dietary supplements both before diagnosis and during treatment in relation to CIPN. Methods: At registration to S0221, 1225 breast cancer patients completed questionnaires regarding the use of multivitamins and supplements before and at diagnosis. A second questionnaire at six months queried use during treatment. Supplement use was evaluated in relation to CIPN, assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with logistic regression for the CTCAE analyses and ordinal regression for the FACT/GOG-Ntx analyses. Results: Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE-adjusted OR = 0.60, 95% CI = 0.42 to 0.87; FACT/GOG-Ntx-adjusted OR = 0.78, 95% CI = 0.61 to 1.00). Use during treatment was marginally inversely associated with CIPN (CTCAE-adjusted OR = 0.73, 95% CI = 0.49 to 1.08; FACT/GOG-Ntx-adjusted OR = 0.77, 95% CI = 0.60 to 0.99). Other supplement use, either before diagnosis or during treatment, was not statistically significantly associated with CIPN. Conclusions: Multivitamin use may be associated with reduced risk of CIPN, although individual dietary supplement use did not appreciably affect risk. Multivitamin use could be a surrogate for other related behaviors that are the actual drivers of the association with reduced CIPN. Without prospective randomized trials of vitamin supplementation, recommendations for use or changes to clinical practice are clearly not warranted.

Ten-Year Outcomes of Patients With Breast Cancer With Cytologically Confirmed Axillary Lymph Node Metastases and Pathologic Complete Response After Primary Systemic Chemotherapy.

IMPORTANCE: The long-term effect of axillary pathologic complete response (pCR) on survival among women with breast cancer treated with primary systemic chemotherapy (PST) is unknown. OBJECTIVE: To assess the long-term effect of axillary pCR on relapse-free survival (RFS) and overall survival (OS) in women with breast cancer with cytologically confirmed axillary lymph node metastases treated with PST. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed the effect of axillary pCR on 10-year OS and RFS among all women who received a diagnosis of breast cancer stages II to III with cytologically confirmed axillary metastases between 1989 and 2007 who received PST at a large US comprehensive cancer center. Women were stratified by post-PST axillary status, and survival outcomes were estimated and compared according to response in the breast and axilla. MAIN OUTCOMES AND MEASURES: Outcomes of interest were RFS and OS. RESULTS: Of 1600 women treated, median (range) age at diagnisis was 49 (21-86) years. A total of 454 (28.4%) achieved axillary pCR. These patients were more likely to have human epidermal growth factor receptor 2 (HER2)-positive and triple-negative disease (P < .001), pCR in the breast (P < .001), high-grade tumors (P < .001), and lower clinical and pathologic T stage (P = .002). Ten-year OS rates were 84% (95% CI, 79%-88%) and 57% (95% CI, 54%-61%) (P < .001) and 10-year RFS rates 79% (95% CI, 74%-83%) and 50% (95% CI, 46%-53%) (P < .001) for patients with axillary pCR and residual axillary disease, respectively. For patients with axillary pCR, 10-year OS rates were 90% (95% CI, 84%-94%) for those with breast pCR and 72% (95% CI, 61%-80%) for those with residual breast disease (P < .001). For patients with residual axillary disease, 10-year OS rates were 66% (95% CI, 56%-74%) for patients with and 56% (95% CI, 52%-60%) for patients without breast pCR (P = .02). Of patients receiving HER2-targeted therapy for HER2-positive disease, 67.1% (100 of 149) achieved axillary pCR; 10-year OS rates were 92% (95% CI, 84%-96%) and 57% (95% CI, 20%-82%) (P = .003) and 10-year RFS rates 89% (95% CI, 81%-94%) and 44% (95% CI, 18%-68%) (P < .001) for those with axillary pCR and residual axillary disease, respectively. CONCLUSIONS AND RELEVANCE: Axillary pCR was associated with improved 10-year OS and RFS. Patients with axillary and breast pCR after PST had superior long-term survival outcomes. Patients undergoing HER2-targeted therapy for HER2-positive disease had high rates of axillary pCR, and those with axillary pCR had excellent 10-year OS.

Outcomes of children exposed in utero to chemotherapy for breast cancer.

INTRODUCTION: The incidence of breast cancer diagnosed during pregnancy is expected to increase as more women delay childbearing in the United States. Treatment of cancer in pregnant women requires prudent judgment to balance the benefit to the cancer patient and the risks to the fetus. Prospective data on the outcomes of children exposed to chemotherapy in utero are limited for the breast cancer population. METHODS: Between 1992 and 2010, 81 pregnant patients with breast cancer were treated in a single-arm, institutional review board-approved study with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in the adjuvant or neoadjuvant setting. Labor and delivery records were reviewed for each patient and neonate. In addition, the parents or guardians were surveyed regarding the health outcomes of the children exposed to chemotherapy in utero. RESULTS: In total, 78% of the women (or next of kin) answered a follow-up survey. At a median age of 7 years, most of the children exposed to chemotherapy in utero were growing normally without any significant exposure-related toxicity or health problems. Three children were born with congenital abnormalities: one each with Down syndrome, ureteral reflux or clubfoot. The rate of congenital abnormalities in the cohort was similar to the national average of 3%. CONCLUSIONS: During the second and third trimesters, pregnant women with breast cancer can be treated with FAC safely without concerns for serious complications or short-term health concerns for their offspring who are exposed to chemotherapy in utero. Continued long-term follow-up of the children in this cohort is required. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00510367. Other Study ID numbers: ID01-193, NCI-2012-01578. Registration date: 31 July 2007.

Latest biopsy approach for suspected metastases in patients with breast cancer.

Biopsy of suspected metastases in patients with breast cancer is recommended in the practice guidelines of the National Comprehensive Cancer Network, but not always performed in routine oncology practice, often because of the cost and invasiveness of the procedure. Biopsies can confirm the presence of metastatic disease, reveal unsuspected benign disease or second (non-breast) malignancies and confirm expression of biomarkers, all of which can aid the optimal management of the cancer. Image-guided biopsy has increased the accuracy and safety of the procedure. Here, we aim to provide a practical algorithm for deciding when to perform biopsy of suspected breast cancer metastases, in order to optimize clinical practice. We expect that future clinical trials and standard-of-care practice will increasingly obtain tissue from metastases to assess molecular differences (DNA, RNA, protein) between the primary tumour and metastases. Advances in targeted therapy for breast cancer will be highly dependent on the availability of metastatic tissue. In this article, we provide an up-to-date review of the current issues in biopsy of suspected metastases in patients with breast cancer, including technical details of biopsy, pathology review of biopsy specimens, and interpretation of biopsy findings.

Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN. PATIENTS AND METHODS: A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue), and NTX grade. RESULTS: A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo. CONCLUSION: There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.

Supplement use during an intergroup clinical trial for breast cancer (S0221).

The use of supplements during chemotherapy is controversial, partly due to the potential effect of antioxidants on reduced efficacy of chemotherapy-related cytotoxicity. We examined supplement use among breast cancer patients registered to a clinical trial (SWOG 0221) before diagnosis and during treatment. Patients (n = 1,467) completed questionnaires regarding multivitamin and supplement use at trial registration (baseline) to capture use before diagnosis. Of these patients, 1,249 completed a 6-month followup questionnaire to capture use during treatment. We examined the use of vitamins C, D, E, B6, B12, folic acid, and calcium at these timepoints, as well as physician recommendations regarding supplement use. The use of vitamins C, E, folic acid, and calcium decreased during treatment, while the use of vitamin B6 increased. Five hundred seventy four patients (51 %) received no physician recommendations regarding supplement use. Among the remaining 49, 10 % were advised not to take multivitamins and/or supplements, 7 % were advised to use only multivitamins, and 32 % received recommendations to use multivitamins and/or supplements. Among patients who took vitamin C before diagnosis, those who were advised not to take supplements were >5 times more likely not to use of vitamin C during treatment than those not advised to stop use (OR = 5.27, 95 % CI 1.13-24.6). Previous non-users who were advised to take a multivitamin were nearly 5 times more likely to use multivitamins during treatment compared to those who received no recommendation (OR = 4.66, 95 % CI 2.10-10.3). In this clinical trial for high-risk breast cancer, supplement use generally decreased during treatment. Upon followup from the clinical trial, findings regarding supplement use and survival outcomes will better inform physician recommendations for patients on adjuvant chemotherapy.

Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer.

PURPOSE: We investigated whether capecitabine and docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) or weekly paclitaxel (WP) followed by FEC would improve relapse-free survival (RFS) in operable breast cancer. PATIENTS AND METHODS: In this single-institution study, patients with clinical stages I to IIIC breast cancer were randomly assigned on a 1:1 basis to WP 80 mg/m(2) for 12 weeks followed by fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-100) every 3 weeks for four cycles or docetaxel 75 mg/m(2) on day 1 and capecitabine (XT) 1,500 mg/m(2) on days 1 through 14 every 3 weeks for four cycles followed by FEC for four cycles and stratified by timing of chemotherapy (preoperative v adjuvant). Accrual was stopped short of 930 patients on the basis of a Bayesian predictive calculation that additional accrual would be unlikely to change the qualitative comparison of the two regimens. RESULTS: After enrollment of 601 patients and a median follow-up of 50 months, we observed no improvement in RFS between XT (87.5%; 95% CI, 82.7% to 91.1%) and WP (90.7%; 95% CI, 86.4% to 93.7%; P = .51). In the preoperative group, the pathologic complete response rate was 19.8% and 16.4% in the XT and WP arms, respectively (P = .45). Rates of breast-conserving surgery were similar between the two groups (P = .48). The XT arm had a significantly higher incidence of stomatitis (P < .001), hand-foot syndrome (P < .001), and neutropenic infection (P < .001). CONCLUSION: There was no difference in efficacy between WP and XT as used in this randomized phase III trial. XT was associated with higher GI, skin, and neutropenic-related toxicities.

Short-term biomarker modulation prevention study of anastrozole in women at increased risk for second primary breast cancer.

The selective estrogen receptor modulators (SERM), Tamoxifen and raloxifen reduce risk breast cancer. Patient acceptance of SERMs for breast cancer prevention is low due to toxicities. New agents with a better toxicity profile are needed. Aromatase inhibitors (AI) reduce the risk of contralateral breast cancer and risk of new breast cancer in high risk women. However, the mechanism by which AIs reduce breast risk is not known. Surrogate biomarkers are needed to evaluate the effect of preventive agents. The objective of this prospective short-term prevention study was to evaluate the effect of anastrozole on biomarkers in breast tissue and serum of women at increased risk for developing a contralateral breast cancer. Women with a history of stage I, II breast cancer who started anastrozole for standard adjuvant treatment were eligible. Patients underwent baseline fine needle aspiration of the unaffected breast and serum collection for biomarker analysis before starting anastrozole at 1 mg per oral/day and again at 6 months. Biomarkers included changes in cytology, insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3. Thirty-seven patients were enrolled. There was a significant modulation in serum IGFBP-1 levels between pre- and postsamples (P = 0.02). No change was observed in IGF-1, IGFBP-3, and breast cytology.We showed a significant modulation of IGFBP-1 levels with six months anastrozole. Anastrozole is currently being studied as a prevention agent in a large phase III trial and our results provide support for continued evaluation of IGFBP-1 as a surrogate endpoint biomarker in prospective breast chemoprevention studies.

Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results.

OBJECTIVE: To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer. METHODS: Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m(2); doxorubicin, 50 mg/m(2); cyclophosphamide, 500 mg/m(2)) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m(2); doxorubicin, 60 mg/m(2); cyclophosphamide, 1,000 mg/m(2)) plus G-CSF every 18 days for four cycles. RESULTS: Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm. CONCLUSIONS: A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.

Hot flashes: a review of pathophysiology and treatment modalities.

Many therapies are being studied for the treatment of hot flashes for individuals with cancer, yet few studies have demonstrated safe and effective clinical benefit for those who suffer from this distressing symptom. The purpose of this paper is to assess the current options for the management of hot flashes, examining key endpoints from recent clinical trials and reviewing future directions. Hot flashes are a common stressful symptom for individuals with cancer, particularly women with a history of breast cancer and men with prostate cancer. Lifestyle modifications are proposed as the first step in the management of less severe hot flashes. Several publications have addressed nonhormonal agents as a treatment option for hot flashes. Newer antidepressant and anticonvulsant agents have been studied and show potential in treating vasomotor symptoms. Although many complementary and alternative therapies, including herbal medications and phytoestrogens, have been studied for the treatment of hot flashes, none are clinically recommended at this time. Additionally, further evidence is needed for supportive exercise such as yoga and relaxation techniques. Acupuncture may warrant further investigation in the reduction and severity of hot flashes in both men and women. Hormonal therapies, including estrogens and progestogens, are the most well-known and efficient agents in alleviating hot flashes; however, the safety of these agents is disputable.

Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers.

PURPOSE: The purpose of this study was to identify genes enriched in breast cancer stroma, assess the stromal gene expression differences between estrogen receptor (ER) -positive and -negative cancers, and separately determine their prognostic value in these two subtypes of breast cancers. METHODS: We compared gene expression profiles of pairs of fine-needle (stroma-poor) and core-needle (stroma-rich) biopsies from 37 cancers to identify stroma-associated genes. We defined stromal metagenes and tested their prognostic values in 684 node-negative patients who received no systemic adjuvant therapy and 259 tamoxifen-treated patients. RESULTS: We identified 293 probe sets overexpressed in core biopsies; these included five highly coexpressed gene clusters (metagenes) corresponding to immune functions and extracellular matrix components. These genes showed quantitative and qualitative differences between ER-positive and ER-negative cancers. A B-cell/plasma cell metagene showed strong prognostic value in ER-positive highly proliferative cancers, a lesser prognostic value in ER-negative cancers, and no prognostic value in ER-positive cancers with low proliferation. The hazard ratio for distant relapse in the lowest compared with the highest tertile of the pooled prognostic data set was 4.29 (95% CI, 2.04 to 9.01; P = .001) in ER-positive cancers and 3.34 (95% CI, 1.60 to 6.97; P = .001) in ER-negative cancers. This remained significant in multivariate analysis including routine variables and other genomic prognostic scores. As a result of quantitative differences in this metagene between ER-positive and ER-negative cancers, different thresholds apply in the two subgroups. Other stromal metagenes had inconsistent prognostic value. CONCLUSION: Among ER-negative and ER-positive highly proliferative cancers, a subset of tumors with high expression of a B-cell/plasma cell metagene carries a favorable prognosis.

Manganese superoxide dismutase polymorphism, treatment-related toxicity and disease-free survival in SWOG 8897 clinical trial for breast cancer.

To date, the few studies of associations between a functional polymorphism in the oxidative stress-related gene manganese superoxide dismutase (SOD2) and breast cancer survival have been inconsistent. In a homogeneous patient population from a large cooperative group trial Southwest Oncology Group (SWOG) 8897, we evaluated this polymorphism in relation to both treatment-related toxicity and disease-free survival (DFS). Among 458 women who received cyclophosphamide-containing adjuvant chemotherapy, those with variant C alleles, related to higher antioxidant activity, experienced less grade 3-4 neutropenia (OR = 0.52, 95% CI = 0.29-0.92) but had worse DFS (HR = 1.59, 95% CI = 0.99-2.55) than women with TT genotypes. No associations were observed among 874 women who were followed without adjuvant therapy. Our results are consistent with the hypothesis that women with higher SOD2 antioxidant activity may experience less treatment-related toxicity but shorter time to disease recurrence or death after breast cancer adjuvant chemotherapy, supporting the modifying effects of oxidative stress-related enzymes on cancer treatment toxicity and efficacy.

Phase 2 trial of primary systemic therapy with doxorubicin and docetaxel followed by surgery, radiotherapy, and adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil based on clinical and pathologic response in patients with stage IIB to III breast cancer : long-term results from the University of Texas M. D. Anderson Cancer Center Study ID97-099.

BACKGROUND: This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross-resistant adjuvant chemotherapy. METHODS: Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor-positive patients only). RESULTS: Eighty-eight patients were evaluable. Seventy-four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5-year recurrence-free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5-year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5-year OS rates were 82% for initially operable and 21% for initially inoperable patients (P < or = .001) CONCLUSIONS: Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long-term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS.