Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.

Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Evaluation of the change of outcomes over a 10-year period in patients with stage III colon cancer: pooled analysis of 6501 patients treated with fluorouracil, leucovorin, and oxaliplatin in the ACCENT database.

BACKGROUND: Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over a 10-year period in patients with stage III colon cancer who received this regimen. PATIENTS AND METHODS: Individual patient data from the ACCENT database was used to compare the outcomes in older (1998-2003) and newer (2004-2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade. RESULTS: A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence [3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj) = 0.83 (95% CI, 0.74-0.92), P = 0.0008], disease-free survival (DFS) [3-year rate, 74.7% versus 72.3%; HRadj = 0.88 (0.79-0.98), P = 0.024], survival after recurrence (SAR) [median time, 27.0 versus 17.7 months; HRadj = 0.65 (0.57-0.74), P < 0.0001], and overall survival (OS) [5-year rate, 80.9% versus 75.7%; HRadj = 0.78 (0.69-0.88), P < 0.0001]. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1-3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors. CONCLUSION: Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints. CLINICAL TRIALS NUMBERS: NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.

Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies.

BACKGROUND: Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. PATIENTS AND METHODS: Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. RESULTS: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. CONCLUSIONS: In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. TRIAL IDENTIFICATION NUMBERS: NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803.

BACKGROUND: The ACCENT group previously established disease-free survival (DFS) with 2 or 3 years median follow-up to predict 5 year overall survival (5 year OS) in stage II and III colon cancer. ACCENT further proposed (1) a stronger association between DFS and OS in stage III than II, and (2) 6 or 7 years necessary to demonstrate DFS/OS surrogacy in recent trials. The relationship between end-points in trials with oral fluoropyrimidines, oxaliplatin and irinotecan is unknown. METHODS: Associations between the treatment effect hazard ratios (HRs) on 2 and 3 years DFS, and 5 and 6 years OS were examined in 6 phase III trials not included in prior analyses from 1997 to 2002. Individual data for 12,676 patients were analysed; two trials each tested oxaliplatin, irinotecan and oral treatment versus 5-FU/LV. FINDINGS: Overall association between 2/3 year DFS and 5/6 year OS HRs was modest to poor (simple R² measures: 0.58-0.76, model-based R²: 0.17-0.49). In stage III patients, the association increased (model-based R² ≥ 0.79). Observed treatment effects on 2 year DFS accurately 5/6 year OS effects overall and in stage III patients. INTERPRETATION: In recent trials of cytotoxic chemotherapy, 2 or 3 years DFS HRs are highly predictive of 5 and 6 years OS HRs in stage III but not stage II patients. In all patients the DFS/OS association is stronger for 6 year OS, thus at least 6 year follow-up is recommended to assess OS benefit. These data support DFS as the primary end-point for stage III colon cancer trials testing cytotoxic agents.

Cancer survivorship research: the challenge of recruiting adult long term cancer survivors from a cooperative clinical trials group.

INTRODUCTION: With the growing number of adult cancer survivors, there is increasing need for information that links potential late and long term effects with specific treatment regimens. Few adult cancer patients are treated on clinical trials; however, patients previously enrolled in these trials are an important source of information about treatment-related late effects. METHODS: Focusing on colorectal cancer survivors, we used the database from five phase III randomized clinical trials from the National Surgical Adjuvant Breast & Bowel Project (NSABP) to recruit and enroll long term survivors in a study of late health outcomes and quality of life. We describe the challenges to recruitment of patients more than 5 -20 years after treatment. RESULTS: Sixty-five NSABP treatment sites were invited to enroll patients in the study. Sixty participated with the potential to recruit 2,408 patients. We received registration forms on only 976 patients (41%) of whom 744 (76%) expressed interest in participating and 708 completed interviews (95% of those expressing interest; 29% of total potential sample). There were multiple barriers to recruitment (difficulty locating patients, lack of institutional commitment, lack of patient interest). CONCLUSIONS: Patients treated on clinical trials are an important potential source for examining the late effects of cancer treatments. Retrospective recruitment has substantial limitations. In the future, mechanisms should be established for prospective long-term follow-up to identify and understand the frequency and type of late effects associated with cancer treatments. IMPLICATIONS FOR CANCER SURVIVORS: As cancer patients are living longer, it will be important to learn from participants in clinical trials whether or not specific treatment regimens are associated with any serious late effects.

Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.

CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown. OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999). MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo. RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive. CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

Sentinel lymph node biopsy after neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a developing alternative to axillary dissection and may prove to be accurate in the detection of micrometastases in lymph nodes of breast cancer patients. Limited studies exist in the use of SLNB after neoadjuvant therapy. This study was undertaken to determine the accuracy of SLNB after neoadjuvant chemotherapy. METHODS: Thirty-one patients with stage I or II breast cancer underwent SLNB after neoadjuvant chemotherapy. RESULTS: Lymphatic mapping was performed by radioisotope, blue dye, or both techniques. Sentinel nodes (SN) were identified in 29 patients (93.5%). The SN was positive in 11 patients (38.0%), and was the only positive node in 5 patients (45.5%). There were no false negative SN by hematoxyin and eosin stain or immunohistochemistry (IHC) studies. CONCLUSIONS: Sentinel node identification rate is similar to that in nonneoadjuvant studies. The sentinel node accurately predicted metastatic disease in the axilla. IHC studies failed to detect any additional micrometastases. This diagnostic technique may provide treatment guidance for patients after neoadjuvant therapy.

Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted two sequential randomized clinical trials to aid in resolving uncertainty about the treatment of women with small, localized, mammographically detected ductal carcinoma in situ (DCIS). After removal of the tumor and normal breast tissue so that specimen margins were histologically tumor-free (lumpectomy), 818 patients in the B-17 trial were randomly assigned to receive either radiation therapy to the ipsilateral breast or no radiation therapy. B-24, the second study, which involved 1,804 women, tested the hypothesis that, in DCIS patients with or without positive tumor specimen margins, lumpectomy, radiation, and tamoxifen (TAM) would be more effective than lumpectomy, radiation, and placebo in preventing invasive and noninvasive ipsilateral breast tumor recurrences (IBTRs), contralateral breast tumors (CBTs), and tumors at metastatic sites. The findings in this report continue to demonstrate through 12 years of follow-up that radiation after lumpectomy reduces the incidence rate of all IBTRs by 58%. They also demonstrate that the administration of TAM after lumpectomy and radiation therapy results in a significant decrease in the rate of all breast cancer events, particularly in invasive cancer. The findings from the B-17 and B-24 studies are related to those from the NSABP prevention (P-1) trial, which demonstrated a 50% reduction in the risk of invasive cancer in women with a history of atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS) and a reduction in the incidence of both DCIS and LCIS in women without a history of those tumors. The B-17 findings demonstrated that patients treated with lumpectomy alone were at greater risk for invasive cancer than were women in P-1 who had a history of ADH or LCIS and who received no radiation therapy or TAM. Although women who received radiation benefited from that therapy, they remained at higher risk for invasive cancer than women in P-1 who had a history of LCIS and who received placebo or TAM. Thus, if it is accepted from the P-1 findings that women at increased risk for invasive cancer are candidates for an intervention such as TAM, then it would seem that women with a history of DCIS should also be considered for such therapy in addition to radiation therapy. That statement does not imply that, as a result of the findings presented here, all DCIS patients should receive radiation and TAM. It does suggest, however, that, in the treatment of DCIS, the appropriate use of current and better therapeutic agents that become available could diminish the significance of breast cancer as a public health problem.

Distinctive patterns of Her-2/neu, c-myc, and cyclin D1 gene amplification by fluorescence in situ hybridization in primary human breast cancers.

BACKGROUND: Human solid tumors undergo clonal evolution as they progress, but evidence for specific sequences of genetic changes that occur in individual tumors and are recapitulated in other tumors is difficult to obtain. METHODS: Patterns of amplification of Her-2/neu, c-myc, and cyclin D1 were determined by fluorescence in situ hybridization (FISH) in relation to the presence of p53 dysfunction and ploidy in 60 primary human breast cancers. RESULTS: We show that there are clusters of genophenotypic abnormalities that distinguish lobular breast cancers from nonlobular tumors; that cyclin D1 amplification occurs prior to the divergence of lobular breast cancers from nonlobular cancers; that p53 dysfunction, Her-2/neu amplification, and c-myc amplification are characteristic features of nonlobular breast cancers, but not of lobular breast cancers; and that the frequencies of amplification of all three oncogenes examined increase progressively with increasing aneuploidy, but that each gene exhibits a different profile of increasing amplification in relation to tumor progression. Early amplification of c-myc appears to be an especially prominent feature of hypertetraploid/hypertetrasomic tumors. CONCLUSIONS: The data suggest that in tumors containing multiple abnormalities, these abnormalities often accumulate in the same cells within each tumor. Furthermore, the same patterns of accumulation of multiple genophenotypic abnormalities are recapitulated in different tumors.

Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial.

BACKGROUND: Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy. When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events since our last report, an update of the B-14 study is appropriate. METHODS: Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to receive placebo (n = 579) or tamoxifen (n = 593). Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test. Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values were two-sided. RESULTS: Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P =.03), RFS = 94% versus 92% (P =.13), and survival = 94% versus 91% (P =.07), respectively. The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics. CONCLUSION: Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes.

Fifteen-year prognostic discriminants for invasive breast carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol-06.

BACKGROUND: This report updated previous findings, at the 15-year mark, of the National Surgical Breast and Bowel Project (NSAPB) Protocol B-06 with respect to the treatment of invasive breast carcinoma and the effects of pathologic features and the effects of some clinical features on its natural history. METHODS: Thirty-one pathologic and 6 clinical features that were observed in a pathologic subset of 1039 evaluable patients were assessed as to their value in predicting survival, in predicting ipsilateral breast tumor recurrence (IBTR), and in predicting the necessity for local breast irradiation after lumpectomy. The patients had been randomly assigned to treatment by lumpectomy without local irradiation or to treatment by lumpectomy with local irradiation of the breast. A traditional and another statistical method were used for this purpose. RESULTS: Multivariate analyses revealed that the presence of IBTR, race, histologic tumor type, nodal status, nuclear grade, and blood vessel invasion affected survival independently. Treatment, patient age, nuclear grade, presence of intraductal carcinoma, and a lymphocytic tumor infiltrate were features that predicted IBTR by multivariate analyses. Irradiation reduced IBTR from 36% to 12% in the analyzed cohort. A test of interaction failed to reveal any pathologic or clinical feature that might have allowed for the omission of local irradiation of the breast after lumpectomy. CONCLUSIONS: In addition to the influence of pathologic and clinical features on patient survival and IBTR, the site, histopathologic features, and time of occurrence of the latter allowed for insights into some important biologic considerations concerning invasive breast carcinoma.

National Surgical Adjuvant Breast and Bowel Project trials in colon cancer.

During the last decade, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has completed six adjuvant chemotherapy trials comparing different adjuvant therapy regimens or adjuvant therapy versus surgery alone. A seventh trial is ongoing. These trials have contributed to defining the role of adjuvant therapy in colon cancer. Patients eligible for inclusion in NSABP trials had been diagnosed as having stage II or III colon cancer with no evidence of gross residual or metastatic disease. The follow-up strategies were similar in the reported trials with follow-up every 3 months for the first 2 years, then every 6 months for the next 3 to 5 years, and annually thereafter. The NSABP C-01 protocol was a three-arm trial comparing an adjuvant semustine/vincristine/5-fluorouracil (5-FU) regimen (MOF) to a Bacille Calmette-Guerin treatment, and to surgery alone. The C-02 protocol investigated whether portal vein infusion of 5-FU improved survival outcome compared with surgery alone. Protocol C-03 compared a semustine/vincristine/5-FU regimen to a 5-FU plus leucovorin (LV) (5-FU/LV) regimen. The NSABP C-04 protocol was a three-arm trial comparing 5-FU/LV, 5-FU plus levamisole, and 5-FU/LV plus levamisole. The NSABP C-05 trial compared 5-FU/LV to 5-FU/LV plus alpha-interferon. Results of NSABP C-01, C-02, C-03, C-04, and C-05 trials are summarized in this report. Patient accrual has completed in the NSABP C-06 trial comparing 5-FU/LV with oral tegafur and plus uracil leucovorin. The NSABP is currently conducting another trial (C-07) comparing 5-FU/LV with 5-FU/LV plus oxaliplatin. The role of adjuvant chemotherapy in stage II colon cancer is also discussed in this report. A recent pooled analysis of studies C-01, C-02, C-03, and C-04 has indicated that the relative treatment benefit in stage II disease is at least equal to the benefit in stage III colon cancers, and concluded that adjuvant chemotherapy also should be considered as the standard of care for stage II colon cancer patients.

Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes.

BACKGROUND: Uncertainty about prognosis and treatment of axillary lymph node-negative patients with estrogen receptor (ER)-negative or ER-positive invasive breast tumors of 1 cm or less prompted the analysis of data from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. METHODS: Two hundred thirty-five patients with ER-negative tumors and 1024 patients with ER-positive tumors were identified in these trials. Patients with ER-negative tumors received surgery alone or surgery and chemotherapy. Patients with ER-positive tumors received surgery alone; surgery and tamoxifen; or surgery, tamoxifen, and chemotherapy. End points were relapse-free survival (RFS), event-free survival, and overall survival. A result was considered to be statistically significant with a P value of.05 or less; all statistical tests were two-sided. RESULTS: The 8-year RFS of women with ER-negative tumors who received surgery alone or with chemotherapy was 81% and 90%, respectively (P = .06). Survival was similar in both groups (93% and 91%; P = .65). The 8-year RFS of women with ER-positive tumors was 86% after surgery alone, 93% when tamoxifen was added (P = .01), and 95% after the addition of tamoxifen and chemotherapy (P = .07 compared with tamoxifen). Survival in the three groups was 90%, 92% (P = .41), and 97%, respectively. The difference between the latter two groups was significant (P = .01). Regardless of ER status or treatment, overall mortality was 8%; one half of the deaths were related to breast cancer. Several covariates affected the risk of recurrence in ER-negative and ER-positive patients. Risk was greater in women with tumors of 1 cm than in those with tumors of less than 1 cm, in women aged 49 years or younger than in those aged 50 years or older, and in women with infiltrating ductal or lobular carcinoma than in those with other histologic tumor types. CONCLUSIONS: Chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes.

Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

The role of tamoxifen in breast cancer prevention: issues sparked by the NSABP Breast Cancer Prevention Trial (P-1).

The Breast Cancer Prevention Trial (P-1: BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized 13,388 women, > or = 35 years of age, at increased risk for breast cancer [> or = 1.66% by Gail model criteria or with a history of lobular carcinoma in situ (LCIS)] to 5 years of tamoxifen or placebo. A 49% reduction (P < 0.00001) in invasive breast cancers occurred, 175 with placebo versus 89 with tamoxifen, mainly among estrogen receptor (ER)-positive tumors (130 with placebo vs. 41 with tamoxifen). The major toxicities of tamoxifen were endometrial cancer (15 with placebo vs. 36 with tamoxifen) and thromboembolic disease, both predominantly in women who were > or = 50 years old. Ramifications emerging from the P-1 results regarding the efficacy and toxicities of preventive tamoxifen include the following: (1) Does tamoxifen induce more virulent breast cancers? (2) Does tamoxifen induce more virulent endometrial cancers? (3) Tamoxifen is especially efficacious in reducing breast cancer risk in LCIS (18 invasive breast cancers with placebo vs. 8 with tamoxifen group) and atypical ductal hyperplasia (AH) (23 invasive breast cancers with placebo vs. 3 with tamoxifen). (4) Does tamoxifen reduce breast cancer risk in women at increased risk due to genetic mutations? (5) How can we prevent tamoxifen-resistant breast cancers? (6) What do the BCPT results tell us about who should take preventive tamoxifen? In its ongoing effort to lower the incidence of breast cancer, the NSABP is now implementing its second breast cancer prevention trial, the Study of Tamoxifen and Raloxifene (STAR), which is comparing the two agents with regard to efficacy and toxicity.

Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer.

Before 1989, credible information about the treatment of breast cancer was derived mainly from randomized clinical trials that enrolled women with either metastatic (stage IV); locally advanced (stage III); or primary, operable, axillary lymph node-positive (stage II) disease. This report provides information from six recent National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving lymph node-negative (stage I) patients. Findings from NSABP B-13 demonstrated, through 14 years of follow-up, improvements in disease-free survival (DFS) and overall survival from methotrexate and fluorouracil (MF), regardless of age, in women with estrogen receptor (ER)-negative tumors. Results from NSABP B-19, which was conducted with similar patients, demonstrated, through 8 years, a greater overall DFS and survival advantage with cyclophosphamide and MF (CMF) than that observed with MF. Findings from NSABP B-23, in which patients similar to those in B-13 and B-19 were randomly assigned to receive CMF plus placebo, CMF plus tamoxifen (TAM), doxorubicin (Adriamycin) and cyclophosphamide (AC) plus placebo, or AC plus TAM, demonstrated no difference in relapse-free survival (RFS) or overall survival among the four groups through 5 years, either for all patients or relative to age. NSABP B-14, which was carried out in women with ER-positive tumors, compared the outcomes of those who received either placebo or TAM. Through 14 years, superior DFS and overall survival advantages, as well as a reduction in contralateral breast cancer, were observed with TAM. No additional benefit resulted from TAM administration beyond 5 years. Findings from NSABP B-20, a second study conducted in patients with ER-positive tumors, showed, after 8 years, both a DFS and an overall survival advantage from TAM plus either MF or CMF over that achieved with TAM alone. A recent meta-analysis in women with negative lymph nodes and either ER-negative or ER-positive tumors of less than or equal to 1 cm in size was conducted using patients from five NSABP trials. After 8 years, the RFS in women with ER-negative tumors was greater in the group treated with surgery and chemotherapy than in those who underwent surgery alone. In women with ER-positive tumors, RFS and overall survival advantages were observed from the addition of chemotherapy to TAM when that treatment regimen was compared with TAM alone. In addition, evidence has been presented from NSABP B-21, a trial evaluating radiation therapy (XRT) and/or TAM for the prevention of ipsilateral breast tumor recurrence (IBTR) after lumpectomy in women with tumors less than or equal to 1 cm. Findings have shown that XRT is superior to TAM and that XRT + TAM is superior to XRT alone for preventing IBTR. The findings demonstrate that chemotherapy and/or hormonal therapy is effective for the management of women with negative axillary lymph nodes and either ER-negative or ER-positive tumors. Because it also has been proven effective in women with tumors less than or equal to 1 cm, such therapy might also be considered in the treatment of that patient population.

Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18.

National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was initiated in 1988 to determine whether four cycles of doxorubicin/cyclophosphamide given preoperatively improve survival and disease-free survival (DFS) when compared with the same chemotherapy given postoperatively. Secondary aims included the evaluation of preoperative chemotherapy in downstaging the primary breast tumor and involved axillary lymph nodes, the comparison of lumpectomy rates and rates of ipsilateral breast tumor recurrence (IBTR) in the two treatment groups, and the assessment of the correlation between primary tumor response and outcome. Initially published findings were based on a follow-up of 5 years; this report updates results through 9 years of follow-up. There continue to be no statistically significant overall differences in survival or DFS between the two treatment groups. Survival at 9 years is 70% in the postoperative group and 69% in the preoperative group (P =.80). DFS is 53% in postoperative patients and 55% in preoperative patients (P =.50). A statistically significant correlation persists between primary tumor response and outcome, and this correlation has become statistically stronger with longer follow-up. Patients assigned to preoperative chemotherapy received notably more lumpectomies than postoperative patients, especially among patients with tumors greater than 5 cm at study entry. Although the rate of IBTR was slightly higher in the preoperative group (10.7% versus 7.6%), this difference was not statistically significant. Marginally statistically significant treatment-by-age interactions appear to be emerging for survival and DFS, suggesting that younger patients may benefit from preoperative therapy, whereas the reverse may be true for older patients.