An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node (SN) biopsy ...(SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided.
In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0i+, ≤ 0.2 mm), were considered positive. The optimal SNB identification rate (IR) ≥ 90% and false-negative rate (FNR) ≤ 10% were predetermined.
From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was 87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4% to 14.4%). If SN ypN0(i+)s had been considered negative, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially avoid CND.
In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR was 87.6%, and in the presence of a technical failure, axillary node dissection should be performed. We recommend that SN evaluation with IHC be further evaluated before being included in future guidelines on the use of SNB after NAC in this setting.
Background: Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen ...receptor–positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings. Methods: Women (n = 13 388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. Results: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk. Conclusions: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.
This study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and ...overall survival (OS).
Women with operable breast cancer (N = 2,411) were randomly assigned to receive preoperative AC followed by surgery, AC followed by T and surgery, or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2,404 patients with follow-up was 77.9 months.
Addition of T to AC did not significantly impact DFS or OS. There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events (P = .0034). Preoperative T, but not postoperative T, significantly improved DFS in patients who had a clinical partial response after AC (hazard ratio HR = 0.71; 95% CI, 0.55 to 0.91; P = .007). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001). Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001).
The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.
Experience with sentinel node biopsy (SNB) after neoadjuvant chemotherapy is limited. We examined the feasibility and accuracy of this procedure within a randomized trial in patients treated with ...neoadjuvant chemotherapy.
During the conduct of National Surgical Adjuvant Breast and Bowel Project trial B-27, several participating surgeons attempted SNB before the required axillary dissection in 428 patients. All underwent lymphatic mapping and an attempt to identify and remove a sentinel node. Lymphatic mapping was performed with radioactive colloid (14.7%), with lymphazurin blue dye alone (29.9%), or with both (54.7%).
Success rate for the identification and removal of a sentinel node was 84.8%. Success rate increased significantly with the use of radioisotope (87.6% to 88.9%) versus with the use of lymphazurin alone (78.1%, P = .03). There were no significant differences in success rate according to clinical tumor size, clinical nodal status, age, or calendar year of random assignment. Of 343 patients who had SNB and axillary dissection, the sentinel nodes were positive in 125 patients and were the only positive nodes in 70 patients (56.0%). Of the 218 patients with negative sentinel nodes, nonsentinel nodes were positive in 15 (false-negative rate, 10.7%; 15 of 140 patients). There were no significant differences in false-negative rate according to clinical patient and tumor characteristics, method of lymphatic mapping, or breast tumor response to chemotherapy.
These results are comparable to those obtained from multicenter studies evaluating SNB before systemic therapy and suggest that the sentinel node concept is applicable following neoadjuvant chemotherapy.
We lack comprehensive information about the extent of out-of-pocket costs after diagnosis of early breast cancer and their effects on the family's financial situation.
This longitudinal study ...assessed out-of-pocket costs and wage losses during the first year after diagnosis of early breast cancer among Canadian women and spouses. Out-of-pocket costs for treatments and follow-up, consultations with other practitioners, home help, clothing, and natural health products were estimated, with information collected from telephone interviews. Generalized linear models were used to identify women at risk of having higher costs and the effects of out-of-pocket costs on perceptions of the family's financial situation.
Overall, 829 women (participation, 86.2%) and 391 spouses participated. Women's median net out-of-pocket costs during the year after diagnosis were $1002 (2003 Canadian dollars; mean = $1365; SD = $1238), and 74.4% of these costs resulted from treatments and follow-up. Spouses' median costs were $111 (mean = $234; SD = $320), or 9% of couples' total expenses. In multivariable analyses, the percentage of women with out-of-pocket costs of $1773 or more (upper quartile) was statistically significantly associated with higher education, working at diagnosis, living more than 50 km from the hospital where surgery was performed, and having two and three different types of adjuvant treatment (all 2-sided P values ≤ .01). However, when considered simultaneously with wage losses, out-of-pocket costs were not associated with perceived deterioration in the family's financial situation; rather, wage losses were the driving factor.
Overall, out-of-pocket costs from breast cancer for the year after diagnosis are probably not unmanageable for most women. However, some women were at higher risk of experiencing financial burden resulting from these costs.
Summary Background Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without ...BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. Methods In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov , number NCT00679783. Findings 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22–64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14–38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 70% of patients with ovarian cancer, 13 50% of patients with breast cancer), nausea (42 66% and 16 62%), vomiting (25 39% and nine 35%), and decreased appetite (23 36% and seven 27%). Interpretation Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed. Funding AstraZeneca.
CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the ...effects of combination palbociclib plus letrozole as neoadjuvant therapy.
Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase.
Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v -0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia.
Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.
Summary Background Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The ...aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects. Methods NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤49 years, ≥50 years), clinical tumour size (≤2·0 cm, 2·1–4·0 cm, ≥4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1–126·7). This study is registered with ClinicalTrials.gov , number NCT00003830. Findings 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96–1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4–93·3) in group 1 and 90·3% (88·8–91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90–1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5–84·4) in group 1 and 81·5% (79·6–83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye. Interpretation Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. Funding US Public Health Service, National Cancer Institute, and Department of Health and Human Services.
Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab ...adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer.
A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks.
At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab CRxT
89.2% with CRx alone; hazard ratio HR, 0.98; 95% CI, 0.76 to 1.25;
= .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50;
= .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95;
= .15). There were no unexpected toxicities from the addition of trastuzumab to CRx.
The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
The addition of bevacizumab to neoadjuvant combination chemotherapy significantly increased the percentage of patients with a pathological complete response. The effect was stronger in the ...estrogen-receptor–positive subgroup than in the hormone-receptor–negative subgroup.
Neoadjuvant chemotherapy has become established as a reasonable alternative to adjuvant chemotherapy for operable breast cancer, since it can increase the rates of breast-conserving surgery
1
–
3
and decrease the need for complete axillary lymph-node dissection.
4
–
6
Neoadjuvant chemotherapy also offers the potential for rapidly testing regimens that may improve response rates and therefore may be likely to improve the outcomes in patients. Although alterations in neoadjuvant chemotherapy that increase the rates of pathological complete response may not necessarily improve survival,
5
,
7
the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial (ClinicalTrials.gov number, NCT00002707) of neoadjuvant . . .
PDF
