Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial.

PURPOSE: Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS: Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician's choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS: The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer-specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor-negative patients (HR, 0.66; P = .02), but not among hormone receptor-positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION: With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor-negative disease. Competing risks in this older population dilute overall survival benefits.

Assessment of Quality of Life and Treatment Outcomes of Patients With Persistent Postchemotherapy Alopecia.

Importance: Persistent alopecia occurs in a subset of patients undergoing chemotherapy, yet the quality of life (QOL) of these patients and their response to therapy have not been described in a large patient cohort. Objective: To characterize the clinical presentation of patients with persistent chemotherapy-induced alopecia (pCIA) or endocrine therapy-induced alopecia after chemotherapy (EIAC) and their QOL and treatment outcomes. Design, Setting, and Participants: A retrospective multicenter cohort of 192 women with cancer treated with cytotoxic agents who received a clinical diagnosis of persistent alopecia (98 with pCIA and 94 with EIAC) between January 1, 2009, and July 31, 2017, was analyzed. All patients were from the dermatology service in 2 comprehensive cancer centers and 1 tertiary-care hospital. Data on demographics, chemotherapy regimens, severity, clinical patterns, and response to hair-growth promoting agents were assessed. Data from the Hairdex questionnaire were used to assess the QOL of patients with alopecia. Main Outcomes and Measures: The clinical presentation, response to dermatologic therapy, and QOL of patients with pCIA were assessed and compared with those of patients with EIAC. Results: A total of 98 women with pCIA (median age, 56.5 years [range, 18-83 years]) and 94 women with EIAC (median age, 56 years [range, 29-84 years]) were included. The most common agents associated with pCIA were taxanes for 80 patients (82%); the most common agents associated with EIAC were aromatase inhibitors for 58 patients (62%). Diffuse alopecia was predominant in patients with pCIA compared with patients with EIAC (31 of 75 [41%] vs 23 of 92 [25%]; P = .04), with greater severity (Common Terminology Criteria for Adverse Events, version 4.0, grade 2) among patients with pCIA (29 of 75 [39%] vs 12 of 92 [13%]; P < .001). A negative emotional effect was reported by both groups. After treatment with topical minoxidil or spironolactone, moderate to significant improvement was observed for 36 of 54 patients with pCIA (67%) and for 32 of 42 patients with EIAC (76%). Conclusions and Relevance: Persistent chemotherapy-induced alopecia is frequently more severe and diffuse when compared with EIAC, and both groups of patients experienced a negative effect. A modest benefit was observed with dermatologic therapy. Additional studies are warranted to develop effective strategies for prevention and effective therapy for pCIA and EIAC.

Phase II Study of Weekly Paclitaxel with Trastuzumab and Pertuzumab in Patients with Human Epidermal Growth Receptor 2 Overexpressing Metastatic Breast Cancer: 5-Year Follow-up.

BACKGROUND: Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up. MATERIALS AND METHODS: In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. RESULTS: From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. CONCLUSION: With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. IMPLICATIONS FOR PRACTICE: The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.

Sleep problems in breast cancer survivors 1-10 years posttreatment.

ABSTRACTObjective:Sleep can affect quality of life (QoL) during cancer survivorship, and symptoms related to poor sleep can be exacerbated. We examined the prevalence, severity, and nature of subjective sleep complaints in women surviving stage I-III breast cancer who were 1-10 years posttreatment. We also examined the demographic, medical, physical, and psychosocial correlates of poor sleep in these women in order to identify the subgroups that may be most in need of intervention. METHOD: A total of 200 patients at a comprehensive cancer center who were 1-10 years posttreatment for primary stage I-III breast cancer with no evidence of disease at the time of enrollment completed a battery of questionnaires on demographics, sleep, physical symptoms, mood, cancer-specific fears, and QoL. RESULTS: The women had a mean age of 57 years (SD = 10.0), with a mean of 63.3 months (SD = 28.8) of post-cancer treatment. Some 38% of these patients were identified as having poor-quality sleep. Women with poor sleep took longer to fall asleep, had more awakenings, and acquired 2 hours less sleep per night than those with good sleep. They also had a lower QoL, greater severity of pain, more concerns about health and recurrence, and increased vasomotor symptoms (p < 0.05). Daytime sleepiness and depression were found to be not significantly correlated with sleep quality. SIGNIFICANCE OF RESULTS: Many breast cancer survivors had severe subjective insomnia, and several breast cancer survivor subgroups were identified as having members who might be most in need of sleep-improvement interventions. Addressing physical symptoms (e.g., vasomotor symptoms and pain) and providing education about the behavioral, social, environmental, and medical factors that affect sleep could result in substantial improvement in the life course of breast cancer survivors.

The effects of soy supplementation on gene expression in breast cancer: a randomized placebo-controlled study.

BACKGROUND: There are conflicting reports on the impact of soy on breast carcinogenesis. This study examines the effects of soy supplementation on breast cancer-related genes and pathways. METHODS: Women (n = 140) with early-stage breast cancer were randomly assigned to soy protein supplementation (n = 70) or placebo (n = 70) for 7 to 30 days, from diagnosis until surgery. Adherence was determined by plasma isoflavones: genistein and daidzein. Gene expression changes were evaluated by NanoString in pre- and posttreatment tumor tissue. Genome-wide expression analysis was performed on posttreatment tissue. Proliferation (Ki67) and apoptosis (Cas3) were assessed by immunohistochemistry. RESULTS: Plasma isoflavones rose in the soy group (two-sided Wilcoxon rank-sum test, P < .001) and did not change in the placebo group. In paired analysis of pre- and posttreatment samples, 21 genes (out of 202) showed altered expression (two-sided Student's t-test, P < .05). Several genes including FANCC and UGT2A1 revealed different magnitude and direction of expression changes between the two groups (two-sided Student's t-test, P < .05). A high-genistein signature consisting of 126 differentially expressed genes was identified from microarray analysis of tumors. This signature was characterized by overexpression (>2-fold) of cell cycle transcripts, including those that promote cell proliferation, such as FGFR2, E2F5, BUB1, CCNB2, MYBL2, CDK1, and CDC20 (P < .01). Soy intake did not result in statistically significant changes in Ki67 or Cas3. CONCLUSIONS: Gene expression associated with soy intake and high plasma genistein defines a signature characterized by overexpression of FGFR2 and genes that drive cell cycle and proliferation pathways. These findings raise the concerns that in a subset of women soy could adversely affect gene expression in breast cancer.

Phase III double-blind, placebo-controlled, prospective randomized trial of adjuvant tamoxifen vs. tamoxifen and fenretinide in postmenopausal women with positive receptors (EB193): an intergroup trial coordinated by the Eastern Cooperative Oncology Group.

Fenretinide and tamoxifen have additive antitumor effects preclinically. We performed a randomized, placebo-controlled, double-blind adjuvant trial in breast cancer patients treated for 5 years with tamoxifen, with or without fenretinide. Between October 1995 and October 1999, 426 postmenopausal women with hormone receptor-positive breast cancer were randomized. Patients were monitored for efficacy and toxicity. Four hundred and nineteen patients were evaluable. The study was terminated early due to slow accrual. There were no significant differences between treatment groups in DFS, TTR or survival. More patients stopped treatment early on the fenretinide arm than on placebo (P = 0.02). Grade 3/4 toxicities, including visual problems and musculoskeletal complaints were more common in patients receiving fenretinide (P = 0.007). A Night Blindness Questionnaire was used to monitor nyctalopia, which was slightly, but not significantly, more common on fenretinide. In this underpowered study, no significant difference was observed in efficacy between treatment groups. This trial provides important toxicity information about fenretinide, a retinoid that has been used in the prevention setting, because it is the only placebo-controlled, double-blind randomized study ever performed.

Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer.

PURPOSE: Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule. PATIENTS AND METHODS: Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon's 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%. RESULTS: The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals. CONCLUSION: Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.

Impact of high-dose chemotherapy on the ability to deliver subsequent local-regional radiotherapy for breast cancer: analysis of Cancer and Leukemia Group B Protocol 9082.

PURPOSE: To report, from Cancer and Leukemia Group B Protocol 9082, the impact of high-dose cyclophosphamide, cisplatin, and BCNU (HD-CPB) vs. intermediate-dose CPB (ID-CPB) on the ability to start and complete the planned course of local-regional radiotherapy (RT) for women with breast cancer involving >or=10 axillary nodes. METHODS AND MATERIALS: From 1991 to 1998, 785 patients were randomized. The HD-CPB and ID-CPB arms were balanced regarding patient characteristics. The HD-CPB and ID-CPB arms were compared on the probability of RT initiation, interruption, modification, or incompleteness. The impact of clinical variables and interactions between variables were also assessed. RESULTS: Radiotherapy was initiated in 82% (325 of 394) of HD-CPB vs. 92% (360 of 391) of ID-CPB patients (p = 0.001). On multivariate analyses, RT was less likely given to patients who were randomized to HD treatment (odds ratio [OR] = 0 .38, p < 0.001), older (p = 0.005), African American (p = 0.003), postmastectomy (p = 0.02), or estrogen receptor positive (p = 0.03). High-dose treatment had a higher rate of RT interruption (21% vs. 12%, p = 0.001, OR = 2.05), modification (29% vs. 14%, p = 0.001, OR = 2.46), and early termination of RT (9% vs. 2%, p = 0.0001, OR = 5.35), compared with ID. CONCLUSION: Treatment arm significantly related to initiation, interruption, modification, and early termination of RT. Patients randomized to HD-CPB were less likely to initiate RT, and of those who did, they were more likely to have RT interrupted, modified, and terminated earlier than those randomized to ID-CPB. The observed lower incidence of RT usage in African Americans vs. non-African Americans warrants further study.

Adjuvant chemotherapy in older women with early-stage breast cancer.

BACKGROUND: Older women with breast cancer are underrepresented in clinical trials, and data on the effects of adjuvant chemotherapy in such patients are scant. We tested for the noninferiority of capecitabine as compared with standard chemotherapy in women with breast cancer who were 65 years of age or older. METHODS: We randomly assigned patients with stage I, II, IIIA, or IIIB breast cancer to standard chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide plus doxorubicin) or capecitabine. Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor-positive tumors. A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients. The primary end point was relapse-free survival. RESULTS: When the 600th patient was enrolled, the probability that, with longer follow-up, capecitabine therapy was highly likely to be inferior to standard chemotherapy met a prescribed level, and enrollment was discontinued. After an additional year of follow-up, the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 (95% confidence interval, 1.38 to 3.17; P<0.001). Patients who were randomly assigned to capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were randomly assigned to standard chemotherapy (P=0.02). At 3 years, the rate of relapse-free survival was 68% in the capecitabine group versus 85% in the standard-chemotherapy group, and the overall survival rate was 86% versus 91%. Two patients in the capecitabine group died of treatment-related complications; as compared with patients receiving capecitabine, twice as many patients receiving standard chemotherapy had moderate-to-severe toxic effects (64% vs. 33%). CONCLUSIONS: Standard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older. (ClinicalTrials.gov number, NCT00024102.)

Influence of activation state of ErbB-2 (HER-2) on response to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for stage II, node-positive breast cancer: study 8541 from the Cancer and Leukemia Group B.

PURPOSE: ErbB-2 (human epidermal growth factor receptor 2) overexpression may be predictive of relative resistance and/or sensitivity to specific chemotherapeutic agents. Results from a previous study from the Cancer and Leukemia Group B (CALGB 8541) demonstrated an interaction between ErbB-2 and increasing dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Other studies have suggested that evaluation of the phosphorylated/activated form of ErbB-2 might be more precise in defining the impact of ErbB-2 in breast cancer. We have evaluated tumor tissue sections from CALGB 8541 patients to determine whether the interaction of ErbB-2 with CAF dose is dependent on ErbB-2 activation state, and whether phosphorylated ErbB-2 is an adverse prognostic factor in patients treated with CAF. PATIENTS AND METHODS: Patients were randomly assigned to one of three dosing regimens of CAF. Paraffin samples from 992 of 1,572 patients who participated in CALGB 8541 were available. Of the 570 tumors with any staining for ErbB-2, 488 had tissue available for assay for phosphorylated ErbB-2, which was performed by immunohistochemistry. RESULTS: Of 910 total assessable cases, 112 of 488 ErbB-2-positive cases (23%) stained positively for phosphorylated ErbB-2. The previously described interaction of dosing regimen of CAF with ErbB-2 was not dependent on phosphorylation status of ErbB-2. CONCLUSION: Monitoring phosphorylation of ErbB-2 with an antiphospho-ErbB-2 antibody did not add further precision to identifying those patients most likely to benefit from increased dose of anthracycline-based adjuvant chemotherapy. Favorable outcomes are observed in ErbB-2-overexpressing patients treated with high-dose CAF regardless of ErbB-2 phosphorylation state.

Effect of creatinine clearance on patterns of toxicity in older patients receiving adjuvant chemotherapy for breast cancer.

OBJECTIVE: A number of age-related physiological changes contribute to an increased risk of toxicity of cancer chemotherapy in the elderly. One of the most important of these changes is the progressive decline in renal function with aging. We sought to determine the association between calculated creatinine clearance (CL(CR)) and grade 3 or 4 toxicities during adjuvant chemotherapy in women > or =65 years of age with breast cancer. DESIGN AND METHODS: We identified 1405 patients > or =65 years of age who had been treated for primary invasive breast cancer at Memorial Sloan-Kettering Cancer Center between January 1998 and December 2000. Patients were included in this analysis if they had stage I-III breast cancer and had received adjuvant chemotherapy. Patients were excluded if they had a prior history of breast cancer or chemotherapy, or had no baseline creatinine value available for review. RESULTS: The 126 patients who met our criteria had received either cyclophosphamide, methotrexate and fluorouracil (CMF) [n = 65, mean age 71, range 65-78] or an anthracycline-based regimen (n = 61, mean age 69, range 65-79). The majority of patients (97%) had a normal creatinine. CL(CR), as calculated by the Cockcroft-Gault and Jeliffe formulas, decreased with increasing age (increased age associated with decreased Cockcroft-Gault [p = 0.02]; increased age associated with decreased Jeliffe [p < 0.01]). In multivariate analysis, after controlling for age and co-morbidity, a CL(CR) <50 mL/min by the Cockcroft-Gault formula was associated with an increased risk of fever and neutropenia (odds ratio [OR] 3.60; 95% CI 1.00, 12.94; p = 0.05) and a CL(CR) <50 mL/min by the Jeliffe formula was associated with a trend towards an increased risk of fever and neutropenia (OR 3.30; 95% CI 0.91, 12.33; p = 0.07), grade 3 or 4 haematological toxicity (OR 2.43; 95% CI 0.90, 6.55; p = 0.08), and need for erythropoietin (OR 4.15; 95% CI 0.81, 2.99; p = 0.09). An increase in creatinine (as a continuous variable) was associated with a trend towards an increased risk of grade 3 or 4 haematological toxicity (OR 5.81; 95% CI 0.96, 35.33; p = 0.06). CONCLUSIONS: In this cohort of older breast cancer patients, a decreased CL(CR) and increased creatinine was associated with an increased risk of fever and neutropenia or haematological toxicity. CL(CR) should be considered when determining chemotherapy dosage in the elderly.

Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients.

PURPOSE: HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients. METHODS: This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology. RESULTS: Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (kappa = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy. CONCLUSION: FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.

Patterns of toxicity in older patients with breast cancer receiving adjuvant chemotherapy.

OBJECTIVE: To retrospectively determine the relationship of age to toxicity from adjuvant chemotherapy for breast cancer. DESIGN AND METHODS: We identified 1,405 consecutive patients age 65 or older with primary invasive breast cancer who were seen at Memorial Sloan-Kettering Cancer Center from January 1998 to December 2000. Patients selected from this cohort for analysis were aged 65 or older at diagnosis; received their follow-up care at Memorial Sloan-Kettering Cancer Center; had stage I, II, or III breast cancer; and received adjuvant chemotherapy consisting of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), an anthracycline-based regimen (AC [doxorubicin and cyclophosphamide], or AC-T [AC and paclitaxel or docetaxel]). Exclusion criteria included prior chemotherapy or previous breast cancer. RESULTS: One hundred thirty-two patients were included in this study, with a mean age of 70 (range 65--79). Comorbidity measured by the Charlson comorbidity index was low: score 0 (83%), 1 (12%), 2 (5%); with stages: I(18%), IIA (41%), IIB (27%), IIIA (8%), IIIB (6%), T1Nx (1%). Patients receiving an anthracycline-based regimen were more likely to experience grade 3 or 4 toxicity (p=0. 01), require hospitalization (p<0.001), and/or develop febrile neutropenia (p<0.001). Treatment delays due to myelosuppression occurred more frequently in patients receiving CMF (p<0.001). The type of chemotherapy regimen (anthracycline compared to CMF) was a better predictor for toxicity than increased age or comorbidity score. CONCLUSIONS: In this cohort of older patients with breast cancer, the risk for toxicity from adjuvant chemotherapy depended more on the type of regimen (anthracycline vs. CMF) than the patient's chronological age.

Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer.

PURPOSE: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. EXPERIMENTAL DESIGN: Patients with >/=4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m(2), respectively, x6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m(2)) alternating with docetaxel (35 mg/m(2)) x18. RESULTS: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26-63 years), median number of positive nodes was 9 (range, 4-32), and median tumor size was 2.5 cm (range, 0.6-11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. CONCLUSION: FEC x6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.

Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B.

PURPOSE: Breast cancer heterogeneity dictates lengthy follow-up to assess outcomes. Efficacy differences for three regimens that are based on adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) are presented in this article, but cancer recurrence sites, time of relapse, subsequent primary cancers, and causes of death in the natural history of node-positive breast cancer are emphasized. PATIENTS AND METHODS: Beginning in 1975, 905 patients with node-positive cancer were randomly assigned to receive CMF or two regimens of CMF plus other agents. Median follow-up is 22.6 years. The natural-history analysis was performed on a subset of 814 patients. RESULTS: Eighty percent of the 599 women known to have died, died of metastatic breast cancer. Only 8.5% of the deceased women died of a cause other than breast cancer, a second or third cancer, or adjuvant chemotherapy toxicity. One hundred five women (12.8%) developed other primary cancers, with 49 (46.6%) occurring in the contralateral breast. Therapeutic efficacy differences of the CMF regimens reported earlier have been maintained more than 20 years later. For certain subsets, the five-drug regimen had advantages over CMF. Bone was the most common recurrence site. The longest interval to relapse has been 23.5 years, and 18% of those who relapsed did so more than 10 years later. CONCLUSION: Despite adjuvant chemotherapy, a large majority (80%) of women with node-positive breast cancer die of the disease, and many recurrences develop more than 10 years later. CMF plus vincristine and prednisone provides a benefit compared with CMF, but the magnitude varies with the number of involved nodes. Outcome trends in earlier analyses of this study were maintained even years later.

Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers.

PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Association of angiogenesis and disease outcome in node-positive breast cancer patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil: a Cancer and Leukemia Group B correlative science study from protocols 8541/8869.

PURPOSE: Increased microvessel density (MVD), a reflection of tumor angiogenesis, is associated with diminished relapse-free and overall survival (OS) in several subsets of breast cancer patients. However, the utility of this assay in node-positive patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) has not been well studied. PATIENTS AND METHODS: Immunostaining for factor VIII-related antigen was performed on tissue sections from a subset of node-positive patients who received one of three dose/schedule regimens of CAF during participation in Cancer and Leukemia Group B protocol 8541. Sections from 577 cancers exhibited acceptable tumor and immunostaining quality and were included in the study. Each section was examined quantitatively for MVD as well as non-quantitatively by scoring the presence or absence of a prominent vascular pattern. RESULTS: MVD counts were not associated with relapse-free or OS in univariate analysis. The presence of a prominent plexiform vascular pattern was correlated with decreased OS (P =.0085) in univariate analysis, but this pattern was not an independent prognostic indicator of survival in multivariate analysis. No apparent clinically important interactions between measures of angiogenesis, other prognostic factors, administration of tamoxifen, and chemotherapy dose were observed. CONCLUSION: Assessment of angiogenesis does not provide useful information regarding prognosis in node-positive breast cancer patients treated with adjuvant CAF, nor do these measures predict which patients will benefit from dose intensification or addition of tamoxifen.