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PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHODS: NSABP B-36 was a phase III clinical trial originally designed as a 2x2 factorial study comparing 6 cycles of FEC-100 (5-FU, epirubicin, cyclophosphamide) to 4 cycles of conventional AC (Adriamycin/cyclophosphamide) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS).RESULTS: Between May 2004-July 2008, 2,722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR=1.09; 95% CI 0.92-1.29, p-value=0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR=1.32, 95% CI=1.05-1.66) compared to receptor-negative patients (HR=0.86, 95% CI=0.66-1.11) (treatment-by-receptor status interaction p-value=0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR=1.06; 95% CI 0.84-1.35, p-value=0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group.CONCLUSIONS: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100.ClinicalTrials.gov: NCT00087178

BackgroundNRG 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.MethodsA 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 (15mg/kg every 3weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24months following study entry.ResultsEarly 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 (

Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

The study objectives were to identify key information components that would be the basic content of a brief informational intervention, developed from a population perspective, to empower individual couple members facing breast cancer and to validate the relevance and acceptability of these components.A review of information relevant to couples facing cancer presented in internet sites and documents of national cancer organizations was made to identify information components to include in a brief informational intervention. These information components were framed as messages, that is, very brief sentences or tips. To validate the relevance and acceptability of these messages, six focus groups were conducted in Quebec City and Montreal among women who had had breast cancer and their spouses. Reactions to the messages were synthesized by analyzing the verbatim transcripts.A total of 70 individuals (35 women with an average of 14 months since diagnosis and 35 spouses) participated in the groups. The content of almost all messages was seen as relevant, although nuances and improvements were discussed. However, the message format provoked irritation and will need improvement.Findings provide validation of the relevance, from the viewpoint of women and their spouses, of the message content to be part of a brief informational intervention intended to empower couples as they cope with breast cancer.Couples approved of the idea of being guided in their adjustment to breast cancer. However, the message format requires adaptation and further testing.

To estimate the 15-year survival following a diagnosis of stage I breast cancer among women who carry a BRCA1 mutation and to determine predictors of mortality, including the use of chemotherapy. Patients were 379 women with stage I breast cancer for whom a BRCA1 mutation had been identified, in herself or in a close family member. Patients were followed for up to 15 years from the initial diagnosis of breast cancer. Survival rates were estimated for women by age, tumor size (≤ 1 cm; > 1 cm), ER status (±), and by chemotherapy (yes/no). 42 women died of breast cancer in the follow-up period (11.2 %). Survival rates were similar for women with cancers of size 0-1.0 cm and size 1.1-2.0 cm. Of the 267 women in the study who used chemotherapy, 21 had died (7.9 %) compared to 21 deaths among 112 women who did not receive chemotherapy (18.8 %; p = 0.002). The 15-year survival was 89.4 % for women who received chemotherapy and was 73.1 % for women who did not receive chemotherapy (p = 0.08; log rank). The adjusted hazard ratio for death following a diagnosis of stage I breast cancer associated with chemotherapy was 0.53 (95 % CI 0.28-1.07; p value 0.06) after adjusting for age of diagnosis, tumor size, and estrogen receptor status. This was statistically significant only among women with ER-negative breast cancers (HR = 0.28; 95 % CI 0.10-0.79; p = 0.02). BRCA1 positive women who are treated for stage I breast cancer with chemotherapy have better survival than those who do not receive chemotherapy. The difference cannot be explained by other prognostic factors. All women with invasive breast cancer and a BRCA1 mutation should be considered to be candidates for chemotherapy.

We describe the frequency of, satisfaction with, and characteristics associated with confidant use among patients and their spouse in the year after diagnosis of non-metastatic breast cancer. In a prospective study of 308 women diagnosed in 1996–97 in Quebec and their spouses, participants were interviewed about confidant use 2 weeks, 3 and 12 months after treatment start. Study completion among eligible individuals was high (patients, 86%; spouses, 84%). Compared to before diagnosis when 55% of patients reported confiding in ≥1 individuals, 84% reported confiding since diagnosis when interviewed 2 weeks after treatment start (prevalence ratio (PR2 weeks) = 1.43, p

Germ-line mutations in the TP53 gene are rare, but predispose women to a range of cancer types, including early-onset breast cancer. Breast cancers in women from families with the Li-Fraumeni syndrome often occur before age 30. The prevalence of deleterious TP53 mutations in unselected women with early-onset breast cancer is not precisely known. If mutations were found to be sufficiently common, it might be prudent to offer genetic testing to affected women in this age group. We screened the entire TP53 gene in the germ-line DNA from 95 women of various ethnic groups who were diagnosed with breast cancer before age 30, and who had previously been found to be negative for BRCA1 and BRCA2 mutations. No TP53 mutation was found. This study does not support a policy that TP53 testing should be offered routinely to unselected women with early-onset breast cancer in the absence of a family history of cancer.

Most of the breast cancer susceptibility genes identified to date are involved in DNA repair, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1. RAP80 works upstream of BRCA1 and is essential for the localization of BRCA1 to the site of damaged DNA. To investigate whether or not RAP80 is also a breast cancer susceptibility gene, we sequenced the entire exonic regions of RAP80 in the germline DNA of 152 women with familial breast cancer, who were previously found to be negative for BRCA1 and BRCA2 mutations. No truncating mutation was identified. Eleven potentially deleterious RAP80 variants were identified; these 11 variants were genotyped in 424 more familial cases and in 726 healthy controls. Three novel p.Ala342Thr, p.Met353Thr and p.Tyr575Asp rare missense variants and a novel haplotype composed of two variants in the CpG island (c.-24149G > T and c.-24001A > G) and a variant in the 5'UTR (c.-8A > G) and a variant in the 3'UTR (c.*27A > C) were detected in 26 of 571 (4.6%) individuals with familial breast cancer, compared to 14 of 725 (1.9%) controls (P = 0.01; OR = 2.4, 95% CI = 1.2-5.1). In summary, we did not find truncating mutations of the RAP80 gene to be a cause of familial breast cancer. A novel RAP80 haplotype or rare missense mutations may be associated with a modest increased risk of breast cancer, but this observation needs to be confirmed by additional studies.

Although the connection between diet, lifestyle and hormones suggests that nutritional and lifestyle factors may exert an influence in the etiology of breast cancer (BC), it is not clear whether these factors operate in the same way in women with BRCA1 and BRCA2 (BRCA) gene mutations who already have an elevated BC risk.A case-control study was conducted within a cohort of 80 French-Canadian families with 250 members involving 89 carriers of mutated BRCA gene affected with BC and 48 non-affected carriers. A validated semi-quantitative food frequency questionnaire was used to ascertain dietary intake, and a lifestyle core questionnaire, to gather information on physical activity and other lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in unconditional logistic regression models.After adjustment for age, maximum lifetime body mass index (BMI) and physical activity, a positive association was found between total energy intake and BRCA-related BC risk. OR was 2.76 (95%CI: 1.10-7.02; p=0.026 for trend), when comparing the highest tertile of intake with the lowest. The intake of other nutrients and dietary components was not significantly associated with the risk of BC. Age at the time the subjects reached maximum BMI was significantly related to an elevated BC risk (OR=2.90; 95%CI: 1.01-8.36; p=0.046 for trend). In addition, a direct and significant relationship was noted between maximum weight gain since both age 18 and 30 years and BC risk. The ORs were 4.64 (95%CI: 1.52-14.12; p=0.011 for trend) for weight gain since age 18 years and 4.11 (95%CI: 1.46-11.56; p=0.013 for trend) for weight gain since age 30 years, respectively. No overall association was apparent between BRCA-related BC risk and BMI, smoking, and physical activity.The results of this preliminary study suggest that weight control in adulthood through dietary energy intake restriction is an important factor for the prevention of BRCA-related BC risk.

BackgroundBRCA1andBRCA2account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetranceCHEK2alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population.MethodsThe 14 coding exons ofCHEK2were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques.ResultsTwo variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73).ConclusionThe novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.

Background PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. Methods We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls. Results We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls. Conclusion We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.