Margin Status and Local Recurrence in Phyllodes Tumours of the Breast: A Canadian Series.

BACKGROUND: Phyllodes tumours of the breast are rare fibroepithelial neoplasms with a propensity for recurrence. While surgical excision remains the standard of care, the optimal margin width is an area of active investigation. Recent studies have questioned the necessity for wide, local excision. METHODS: We conducted a retrospective, cohort study of patients with phyllodes tumours treated at our institution between 2003 and 2021. Demographic, histopathological, and recurrence data were captured; malignant phyllodes were excluded. Cox proportional hazard models were used to identify covariates associated with local recurrence. RESULTS: Of 187 patients with phyllodes tumours, 82.9% (n = 155) were classified as benign while 17.1% (n = 32) were borderline. Initial surgical margins were positive in 26.2% (n = 49), < 2 mm in 50.8% (n = 95), and ≥ 2 mm in 23% (n = 43) patients. Among patients with positive margins, 61.2% (n = 30) underwent margin revision. At a median follow-up of 2.9 years, the recurrence rate was 3.7%. On univariate analysis, only a positive margin at the time of initial surgery and not margin width was significantly associated with a higher rate of disease recurrence (hazard ratio [HR] 9.52, 95% confidence interval [CI] 1.85-49.2), as was a size greater than 4 cm on preoperative imaging (HR 10.78, 95% CI 0.97-120.1). Revision of an initially positive margin was not significantly associated with decreased local recurrence (p = 1). CONCLUSIONS: In this large cohort of benign and borderline phyllodes tumours, positive resection margins and not margin width at the initial surgery were associated with a increased recurrence. Individualization of decisions regarding margin reexcision is important.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Population-based analysis of non-operative management and treatment patterns in older women with estrogen receptor-positive breast cancer.

PURPOSE: To examine the proportion of older women with ER + HER2- breast cancer receiving non-operative management versus surgery, and to evaluate the use of axillary staging and adjuvant radiation in this population. METHODS: We queried the SEER database to identify all women aged 70 years or older with stage I-III ER + HER2- invasive breast cancer diagnosed between 2010 and 2016. We evaluated trends in non-operative management, breast surgery, axillary staging, and adjuvant radiation according to age at diagnosis. RESULTS: We identified 57,351 older women with ER + HER2- disease. Overall, 3538 (6.2%) of the cohort underwent non-operative management, 38,452 (67.0%) underwent breast-conserving surgery (BCS), and 15,361 (26.8%) underwent mastectomy. The proportion of patients undergoing non-operative management increased from 2.8% among 70-74-year-old women to 30.1% in those ≥ 90 years old (p < 0.001). In 53,813 women who underwent surgery, 36,850 (68.5%) underwent sentinel lymph node biopsy, while 10,861 (20.2%) underwent axillary lymph node dissection. Subgroup analysis of 29,032 older women undergoing BCS for stage I ER + HER2- breast cancer revealed a 14.2% rate of omission of axillary staging, increasing from 5.3% in those 70-74 years to 67.6% in those ≥ 90 years old (p < 0.001). Receipt of adjuvant radiation occurred in 63.3% of older women following BCS and 18% post-mastectomy, with similar trends towards omission in older age groups. CONCLUSION: Primary breast surgery remains the dominant management strategy for the majority of older women with ER + HER2- breast cancer. Omission of axillary staging and adjuvant radiation are used in a minority of eligible women undergoing breast conservation for early-stage disease.

Oncologic Safety of Sentinel Lymph Node Biopsy Alone After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The oncologic safety of sentinel lymph node biopsy (SLNB) alone for clinically node-positive (cN1-2) patients who convert to pathologic node-negativity (ypN0) after neoadjuvant chemotherapy (NAC) is not well established. METHODS: This study retrospectively identified 244 consecutive patients with a diagnosis of cT1-3cN0-2 breast cancer who underwent NAC followed by SLNB at the authors' institution between 2013 and 2018. The patients were categorized as clinically node-negative (cN0) or cN1-2 before the onset of NAC, and the Kaplan-Meier method was used to compare locoregional and distant recurrence rates after SLNB alone for ypN0 patients. RESULTS: Among 244 patients who underwent NAC followed by surgery with SLNB for axillary staging, 112 (45.9%) were cN0 at presentation, whereas 132 (54.5%) had biopsy-proven cN1-2 disease and converted to cN0 after treatment. Of the patients presenting with cN0 disease, 102 (91.1%) were ypN0 on SLNB pathology compared with 60 cN1/2 patients (45.5%; p < 0.001). Regional nodal irradiation was administered to 5% of the cN0/ypN0 patients compared with 70.7% of the cN1-2/ypN0 patients (p < 0.001). Overall, 211 patients were treated with SLNB alone and had a median follow-up period of 36 months (interquartile range [IQR], 24-53 months). For 101 cN0/ypN0 patients who underwent SLNB alone, the 5-year local and regional recurrence rates were respectively 5.7% (95% confidence interval [CI], 2.4-13.8) and 1% (95% CI 0.1-7.0). For 58 cN1-2/ypN0 patients who underwent SLNB alone, the 5-year local and regional recurrence rates were respectively 4.1% (95% CI 1.0-15.5) and 0%, with no axillary recurrences noted. CONCLUSION: For ypN0 patients, SLNB alone after NAC is associated with low and acceptable short-term axillary recurrence rates. Additional follow-up data from prospective clinical trials are needed to confirm long-term oncologic safety and define optimal local therapy recommendations.

Long-term Peripheral Neuropathy in Breast Cancer Patients Treated With Adjuvant Chemotherapy: NRG Oncology/NSABP B-30.

Background: The long-term effects of chemotherapy are sparsely reported. Peripheral neuropathy (PN) is one of the most frequent toxicities associated with taxane use for the treatment of early-stage breast cancer. We investigated the impact of the three different docetaxel-based regimens and patient characteristics on long-term, patient-reported outcomes of PN and the impact of PN on long-term quality of life (QOL). Methods: The National Surgical Adjuvant Breast and Bowel Project Protocol B-30 was a randomized trial comparing sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T) (AC→T), concurrent ACT, or AT in women with node-positive, early-stage breast cancer. The AC→T group had a higher cumulative dose of T. PN was one of the symptoms assessed in a QOL substudy. Statistical methods included simple and mixed ordinal logistic regression and general linear models. All statistical tests were two-sided. Results: Of 1512 patients, 41.9% reported PN two years after treatment initiation. Treatment with AT and ACT was associated with less severe long-term PN compared with AC→T (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.35 to 0.58; OR = 0.59, 95% CI = 0.46 to 0.75). Preexisting PN, older age, obesity, mastectomy, and greater number of positive nodes were also associated with higher risk of long-term PN. Patients who reported worse PN symptoms at 24 months had statistically significantly worse QOL (Ptrend < .001). Conclusions: The administration of docetaxel is associated with long-term PN. The lower rate of long-term PN in AT and ACT patients might be an important consideration in supporting choosing these therapies for individuals with preexisting neuropathic symptoms or other risk factors for neuropathy.

The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer: NRG Oncology/NSABP Protocol B-40.

BACKGROUND: NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev. METHODS: A total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry. RESULTS: Early surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson, p = 0.11). CONCLUSIONS: Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.

Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy. METHODS: The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ≥60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00053898, and is complete. FINDINGS: Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group. INTERPRETATION: Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ. FUNDING: US National Cancer Institute and AstraZeneca Pharmaceuticals LP.

Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms. METHODS: The study was done at 333 hospitals in North America. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were randomly assigned to receive either tamoxifen (20 mg/day) or anastrazole (1 mg/day) for 5 years, stratified by age (<60 years vs ≥60 years). Patients and investigators were masked to treatment allocation. Patients completed questionnaires at baseline and every 6 months thereafter for 6 years. The primary outcomes were SF-12 physical and mental health component scale scores, and vasomotor symptoms (as per the BCPT symptom scale). Secondary outcomes were vaginal symptoms and sexual functioning. Exploratory outcomes were musculoskeletal pain, bladder symptoms, gynaecological symptoms, cognitive symptoms, weight problems, vitality, and depression. We did the analyses by intention to treat, including patients who completed questionnaires at baseline and at least once during follow-up. This study is registered with ClinicalTrials.gov, NCT00053898. FINDINGS: Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled in the study, of whom 1193 were included in the quality-of-life substudy: 601 assigned to tamoxifen and 592 assigned to anastrozole. We detected no significant difference between treatment groups for: physical health scores (mean severity score 46·72 for tamoxifen vs 45·85 for anastrozole; p=0·20), mental health scores (52·38 vs 51·48; p=0·38), energy and fatigue (58·34 vs 57·54; p=0·86), or symptoms of depression (6·19 vs 6·39; p=0·46) over 5 years. Vasomotor symptoms (1·33 vs 1·17; p=0·011), difficulty with bladder control (0·96 vs 0·80; p=0·0002), and gynaecological symptoms (0·29 vs 0·18; p<0·0001) were significantly more severe in the tamoxifen group than in the anastrozole group. Musculoskeletal pain (1·50 vs 1·72; p=0·0006) and vaginal symptoms (0·76 vs 0·86; p=0·035) were significantly worse in the anastrozole group than in the tamoxifen group. Sexual functioning did not differ significantly between the two treatments (43·65 vs 45·29; p=0·56). Younger age was significantly associated with more severe vasomotor symptoms (mean severity score 1·45 for age <60 years vs 0·65 for age ≥60 years; p=0·0006), vaginal symptoms (0·98 vs 0·65; p<0·0001), weight problems (1·32 vs 1·02; p<0·0001), and gynaecological symptoms (0·26 vs 0·22; p=0·014). INTERPRETATION: Given the similar efficacy of tamoxifen and anastrozole for women older than age 60 years, decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug. For women younger than 60 years old, treatment decisions might be driven by efficacy (favouring anastrozole); however, if the side-effects of anastrozole are intolerable, then switching to tamoxifen is a good alternative. FUNDING: US National Cancer Institute, AstraZeneca Pharmaceuticals.

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

BACKGROUND: NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. METHODS: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. FINDINGS: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). INTERPRETATION: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. FUNDING: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29.

NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97% of patients were ≥50 years; for B-29, 62%. MA.14 patients were 53% lymph node negative (LN-) while B-29 were 100% LN-; 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while B-29 had 53% concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100%. MA.14 patients experienced 5-year DFS of 80% with TAM, 76% with TAM + OCT; B-29 patients had 5-year DFS of 88% for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.

Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial.

BACKGROUND: We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients. METHODS: For this open-label, randomised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer. Each received four cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m(2)) intravenously on days 1, 8, and 15, every 4 weeks. Concurrently with weekly paclitaxel, patients received either trastuzumab (4 mg/kg load, then 2 mg/kg intravenously) weekly until surgery, lapatinib (1250 mg orally) daily until surgery, or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery. After surgery, all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy. Randomisation (ratio 1:1:1) was done centrally with stratification by clinical tumour size, clinical nodal status, hormone-receptor status, and age. The primary endpoint was the pathological complete response in the breast, and analysis was performed on an intention-to-treat population. FINDINGS: Patient accrual started on July 16, 2007, and was completed on June 30, 2011; 529 women were enrolled in the trial. 519 patients had their pathological response determined. Breast pathological complete response was noted in 93 (52·5%, 95% CI 44·9-59·5) of 177 patients in the trastuzumab group, 91 (53·2%, 45·4-60·3) of 171 patients in the lapatinib group (p=0·9852); and 106 (62·0%, 54·3-68·8) of 171 patients in the combination group (p=0·095). The most common grade 3 and 4 toxic effects were neutropenia (29 [16%] patients in the trastuzumab group [grade 4 in five patients (3%), 28 [16%] in the lapatinib group [grade 4 in eight patients (5%)], and 29 [17%] in the combination group [grade 4 in nine patients (5%)]) and grade 3 diarrhoea (four [2%] patients in the trastuzumab group, 35 [20%] in the lapatinib group, and 46 [27%] in the combination group; p<0·0001). Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven (4%) patients in the trastuzumab group, seven (4%) in the lapatinib group, and one (<1%) in the combination group; p=0·185). INTERPRETATION: Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.

Bevacizumab added to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS: We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy. RESULTS: The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS.

BACKGROUND: Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS. METHODS: In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients). RESULTS: Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM. CONCLUSIONS: Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer.

Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS. PATIENTS AND METHODS: Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T. RESULTS: Results from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not. CONCLUSION: B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response.

How patients with less-advanced and more-advanced cancer deal with three death-related fears: an exploratory study.

The means used by cancer patients to cope with each of three death anxieties (i.e., fear of pain and suffering, loneliness, and the unknown) that contribute to their psychological distress have rarely been examined. Differences between cancer patients with Stage I or II disease (Group 1) and Stage III or IV disease (Group 2) were explored. T-tests revealed no difference between the groups. Age-controlled Pearson correlations were used to determine the relationship between all three death anxieties, and some recognized coping devices used by cancer patients, namely, coping styles, optimism, and religiosity/spirituality. Results showed that, for Group 1, avoidant coping correlated positively with fear of the unknown, and social diversion correlated positively with fear of pain and suffering. As for similarities between groups, with the exception of fear of pain and suffering for Group 2, emotion-focused coping correlated positively with all three death anxieties, and optimism correlated negatively with fear of the unknown. The advantage for researchers and clinicians of including measures or evaluation of the death anxieties in their considerations of the psychological distress of cancer patients is discussed.