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.

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.

Screening for BRCA1 and BRCA2 mutations among French-Canadian breast cancer cases attending an outpatient clinic in Montreal.

Study subjects were French-Canadian women with ductal carcinoma in situ (DCIS) or invasive breast cancer (incident or prevalent) who were treated and followed at a single breast cancer clinic affiliated with the Research Center of University of Montreal (CRCHUM), who were either aged less than 50 years at diagnosis or who were 50 years or older and with at least two affected first- or second-degree relatives. Subjects were tested for six founder mutations (three in BRCA1 and three in BRCA2); 1093 eligible cases were tested. Of these, 56 women (5.1%) were mutation carriers, including 43 BRCA2 carriers and 13 BRCA1 carriers. The prevalence of mutations was 5.3% for unselected women aged 50 and less and was 4.6% for familial cases over age 50. The prevalence of mutations was 3.3% for women with DCIS and was 5.3% for women with invasive cancer. It is rational to offer genetic testing to all French-Canadian women diagnosed recently or in the past with either DCIS or invasive breast cancer before age 50 or with familial breast cancer above age 50.

A prospective pilot study investigating the musculoskeletal pain in postmenopausal breast cancer patients receiving aromatase inhibitor therapy.

BACKGROUND: Although arthralgia is a known adverse effect of aromatase inhibitor (ai) treatment in postmenopausal breast cancer patients, few studies have carried out a comprehensive evaluation of the nature, onset, and incidence of musculoskeletal (msk) pain in these patients. We therefore used a pilot study to identify conditions or markers predictive of pain. METHODS: For 24 weeks, we monitored 30 eligible postmenopausal women starting ai therapy. Pre-existing and incident msk conditions and pain were assessed clinically and with ultrasonography of the hands and wrists. In addition, patient questionnaires were used to assess pain before and during ai therapy. Biochemical markers were measured at baseline and at regular intervals after anastrozole therapy began. Gene profiling studies were carried out before and 48 hours after the initial ai administration. RESULTS: Over the 24-week study period, 20 participants (67%) showed no pain symptoms; 5 (17%) experienced low or moderate pain at baseline, which did not increase with ai treatment; and during therapy, 5 (17%) showed exacerbation of pain attributable to osteoarthritis of the hand and to finger flexor tenosynovitis. Although all 30 participants had some degree of msk conditions before anastrozole therapy started, the pre-existing conditions did not necessarily predispose the women to increased pain during anastrozole treatment. Higher levels of urinary N-telopeptides of type i collagen were associated with the groups presenting pain, suggesting a higher extent of pre-existing bone resorption, without significant evolution over the 24-week treatment period. Slightly higher levels of 1,25(OH)(2) vitamin D(3) were observed at baseline in patients with pain increase, but did not significantly change during treatment; however, average levels of 25(OH) vitamin D(3) increased, likely because of supplementation. Although biochemical markers did not discriminate efficiently between pain groups, a signature of 166 genes in peripheral blood mononuclear cells was identified that could stratify patients into the various groups observed in this pilot study. The gene signature was enriched in components of inflammatory signalling and chemokine expression, of antitumoural immunity pathways, and of metabolic response to hormones and xenobiotics, although no clinically significant association could be made in the present study, considering the small number of patients. Nevertheless, the observed trend suggests the feasibility of developing surrogate predictive markers of msk pain. Patient compliance was high in this study and was not affected by pain exacerbation. CONCLUSIONS: Baseline msk assessment showed pre-existing causes for pain in most of the study patients before initiation of the ai. Exacerbation of existing osteoarthritis pain and tenosynovial symptoms was the primary cause of pain increase. Musculoskeletal pain assessment at baseline and prompt treatment of pain symptoms may help to optimize adherence to ai therapy. The value of routinely assessing inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate was not supported by our pilot study. Gene expression profiles in peripheral blood mononuclear cells may be further explored in larger-scale studies as stratification markers to identify patients at risk of developing arthralgia.

The contribution of founder mutations to early-onset breast cancer in French-Canadian women.

In an ethnically-homogeneous population, it is valuable to identify founder mutations in cancer-predisposing genes. Founder mutations have been found in four breast-cancer-predisposing genes in French-Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French-Canadian women with early-onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French-Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7-28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9-67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4-9.1). One-half of the women with a mutation had a first- or second-degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French-Canadian women with early-onset breast cancer. It is reasonable to offer screening for founder mutations to all French-Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population-based screening.

Diet, lifestyle and BRCA-related breast cancer risk among French-Canadians.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families.

The BRCA2 8765delAG mutation was previously reported in hereditary breast cancer families of French Canadian and Yemenite Jewish descent. Haplotype analysis, using six microsatellite markers that span BRCA2 and two intragenic polymorphisms, was performed on 8765delAG mutation carriers to determine if there was evidence that the mutations were identical by descent. The alleles of the microsatellite markers most closely flanking BRCA2 (D13S1697 and D13S1701) were found to be identical in state in all the mutation carriers. However, the disease-associated allele of one of the intragenic markers differed between the Yemenite Jews and French Canadian families, indicating that the 8765delAG mutation has independent origins in these two geographically and ethnically distinct populations.

Prevalence of founder BRCA1 and BRCA2 mutations in unselected French Canadian women with breast cancer.

The frequency of BRCA1 and BRCA2 mutations in women with breast cancer varies according to the age at diagnosis, family history of cancer, and ethnicity/country of origin. We set out to estimate the frequency of seven previously described founder mutations in BRCA1 and BRCA2 in all eligible French Canadian women diagnosed with invasive breast cancer at one Montreal hospital over a 20-month period. One hundred and ninety-two patients were eligible and 127 (66.2%) provided blood for genetic testing. We identified 4 women who carried a founder mutation (3.1%, 95% confidence interval 0.9-7.9%) in this population. Interestingly, all the mutations were in BRCA2. The mean age at diagnosis for mutation carriers was 51.2 years (range 49.1-53.5). Two of these 4 cases were lobular invasive carcinomas and 2 were ductal carcinomas, histological grade 1 or 2. Despite a small tumor size (< or =20 mm), axillary nodal involvement was present in 3 women. Estrogen receptors were strongly expressed in all cases. Two of the 4 cases reported a strong family history of breast cancer, but a family history of site-specific breast cancer was a relatively poor indicator of the presence of BRCA2 mutations. The absence of BRCA1 mutations may be a result of chance, but may also reflect different geographical origins of the most common BRCA1 mutations within the French Canadian population.

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

BACKGROUND: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. METHODS: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. RESULTS: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. CONCLUSIONS: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.

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.

Metastatic axillary lymph node technetium-99m-MIBI imaging in primary breast cancer.

UNLABELLED: Technetium-99m-MIBI scintimammography has been shown to be useful in the detection of primary breast cancer. The purpose of this study was to evaluate the potential role of scintimammography in detecting axillary lymph node involvement in patients undergoing scintimammography to detect primary breast cancer. METHODS: A group of 100 women with breast cancer who were scheduled for a Level I-II axillary dissection were prospectively studied. Scintimammography was performed in all patients before histopathologic confirmation of breast cancer. Two lateral (prone imaging) views and one anterior (supine) planar thoracic view were obtained 10-15 min after the injection of 25-30 mCi 99mTc-MIBI (10 min/view) by using a special breast positioning device (foam cushion) placed over the imaging table. Both of the axilla were included in the field-of-view. Two experienced blinded observers reviewed all cases both from films and from the computer screen with contrast adjustment when needed. The site of intravenous injection of 99mTc-MIBI was known to the interpreters in order to avoid reading any false-positive uptake in the axilla ipsilateral to the injection site. RESULTS: A total of 52 patients had no axillary lymph node involvement (611 negative nodes) while 48 patients had at least one axillary lymph node with metastatic involvement (180/502 positive nodes). The sensitivity of scintimammography in detecting metastatic axillary lymph node involvement was 79.2% (38/48), and the specificity was 84.6% (44/52). The positive and the negative predictive values were 82.6% (38/46) and 81.5% (44/54), respectively. CONCLUSION: This study shows that scintimammography has good diagnostic accuracy for detecting axillary lymph node involvement in patients with breast cancer. This information should be added to the result of standard scintimammography, which requires very minor modifications in order to simultaneously evaluate both of the axilla.

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.

PURPOSE: To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. PATIENTS AND METHODS: Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). RESULTS: Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. CONCLUSION: Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.

Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors.

BACKGROUND: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS: In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS: Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.

Technetium-99m-sestamibi prone scintimammography to detect primary breast cancer and axillary lymph node involvement.

UNLABELLED: The purpose of this study was to evaluate prospectively the sensitivity and specificity of scintimammography in the detection of both primary breast cancer and axillary lymph node involvement. METHODS: Sixty-five consecutive women referred for a suspicious breast lesion on clinical examination and/or with abnormal mammographies suggestive of malignancies were studied with scintimammography using planar prone imaging (with a chest positioning device with semicircular lateral aperture on the imaging table) performed 15 min postinjection of 25-30 mCi 99mTc-sestamibi. Three planar views, right and left lateral prone and anterior supine thoracic views, were obtained (8-10 min/view). The entire breast and ipsilateral axillary region were included in the field of view. Excisional breast biopsy and/or fine needle aspiration cytology were performed in all patients within 4 wk after scintimammography. Axillary node dissection was also performed. RESULTS: The largest primary tumor measured 2 x 3 cm. There were 47 primary breast cancers (8 different histologic types) and 18 benign breast lesions (5 histologic types). The sensitivity of scintimammography for detecting primary breast cancer was 91.5% (43 true-positive, 4 false-negative) and the specificity was 94.4% (17 true-negative, 1 false-positive). Metastatic axillary lymph node involvement was seen in 19 of 41 patients. The sensitivity of scintimammography to detect metastatic lymph nodes was 84.2% (16 true-positive, 3 false-negative) and the specificity was 90.9% (20 true-positive, 2 false-positive). CONCLUSION: This preliminary study confirms the results of some previous reports, which showed the high diagnostic accuracy of scintimammography in detecting breast cancer. This study also shows the potential value of this procedure to detect axillary lymph node involvement as concomitant information.

E5531, a pure endotoxin antagonist of high potency.

Shock due to Gram-negative bacterial sepsis is a consequence of acute inflammatory response to lipopolysaccharide (LPS) or endotoxin released from bacteria. LPS is a major constituent of the outer membrane of Gram-negative bacteria, and its terminal disaccharide phospholipid (lipid A) portion contains the key structural features responsible for toxic activity. Based on the proposed structure of nontoxic Rhodobacter capsulatus lipid A, a fully stabilized endotoxin antagonist E5531 has been synthesized. In vitro, E5531 demonstrated potent antagonism of LPS-mediated cellular activation in a variety of systems. In vivo, E5531 protected mice from LPS-induced lethality and, in cooperation with an antibiotic, protected mice from a lethal infection of viable Escherichia coli.

Recent trends in the management of breast cancer. 2. Occult breast lesions: when and how to perform a biopsy for mammographic abnormalities.

In 1989 the Canadian Cancer Society recommended that women over 50 years of age should undergo mammography as a test for breast cancer in centres dedicated to such programs. This recommendation and others by American societies have increased the number of mammographies done for screening purposes. As a result many mammographic abnormalities are reported by radiologists, who recommend biopsy. The surgeon should review the films with the radiologist and ensure that the anomaly is real. Attention should be given to specific signs of cancer, such as spiculated lesions; however, nonspecific signs of cancer, such as microcalcifications, microlobulation and architectural distortion, should be evaluated carefully before biopsy is carried out. Stereotaxic fine-needle aspiration can decrease the number of surgical biopsies needed. The surgical biopsy should be a one-step, segmental mastectomy done for diagnosis and treatment. The specimen should be oriented, inked and x-rayed and a definitive diagnosis made on paraffin blocks. Frozen sections should not be made of microcalcifications.

[Quality of life of patients after restorative surgery for cancer of the rectum]. / Qualité de vie des patients opérés à visée curative pour un cancer du rectum.

During the last decades surgeons have put a tremendous effort to perform low anterior resection (LAR) as a curative procedure for rectal cancer treated classically by abdomino-perineal resection (APR) and permanent colostomy. A psychological evaluation testing the multi-dimensional concept of quality of life was done in 32 patients (M = 21; F = 11) treated by APR and compared to 28 patients (M = 16; F = 12) treated by LAR. Patients were assessed for quality of life on the following dimensions: physical well-being, psychological well-being, dietary habits, surgical response, social concerns, body image, stress and marital adjustment. Using as covariables social support and time elapsed since surgery, a covariate analysis was used to determine the presence of group ans sex interaction. Patients with LAR had a better body image (p.001), dietary habits (p.003) and tolerance to stress (p.004). Better global quality of life (p.001), physical well being (p.001) and less surgical sequela (p.001) were found with LAR in women only. No significant difference was found on psychological well being, social concerns and marital adjustment in both surgical groups.

Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02.

Between March 1984 and July 1988, 1,158 patients with Dukes' A, B, and C carcinoma of the colon were entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-02. Patients were randomized to either no further treatment following curative resection or to postoperative fluorouracil (5-FU) and heparin administered via the portal vein. Therapy began on day of operation and consisted of constant infusion for 7 successive day. Average time on study was 41.8 months. A comparison between the two groups of patients indicated both an improvement in disease-free survival (74% v 64% at 4 years, overall P = .02) and a survival advantage (81% v 73% at 4 years, overall P = .07) in favor of the chemotherapy-treated group. When compared with the treated group, patients who received no further treatment had 1.26 times the risk of developing a treatment failure and 1.25 times the likelihood of dying after 4 years. Particularly significant was the failure to demonstrate an advantage from 5-FU in decreasing the incidence of hepatic metastases. The liver was the first site of treatment failure in 32.9% of 82 patients with documented recurrences in the control group and in 46.3% of 67 patients who received additional treatment. Therapy is administered via a regional route to affect the incidence of recurrence within the perfused anatomic boundary. Since, in this study, adjuvant portal-vein 5-FU infusion failed to reduce the incidence of hepatic metastases, it may be concluded that its use thus far is not justified. It may also be speculated that the disease-free survival and survival advantages (the latter of borderline significance) are a result of the systemic effects of 5-FU.

Systemic therapy in patients with node-negative breast cancer. A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials.

OBJECTIVE: To determine whether in the previous National Surgical Adjuvant Breast and Bowel Project (NSABP) studies of node-negative breast cancer there were either cohorts of patients with a prognosis favorable enough to preclude using systemic therapy or subsets of patients who failed to benefit from the treatments. DESIGN: Randomized clinical trials with stratification after surgery. SETTING: NSABP trials at institutions in the United States and Canada. PATIENTS: Data were collected on 731 eligible patients (Protocol B-13) with estrogen-receptor-negative tumors who randomly received either no therapy after surgery or sequential methotrexate and fluorouracil (M----F) followed by leucovorin. Data were also collected on 2834 patients (Protocol B-14) with estrogen-receptor-positive tumors who randomly received either placebo or tamoxifen treatment. The percentage of patients surviving disease-free was determined through 4 years of follow-up using life-table estimates. INTERVENTIONS: Protocol B-13 patients received 12 courses of M----F given intravenously on days 1 and 8 every 4 weeks. Leucovorin therapy was begun 24 hours after M----F administration. Protocol B-14 patients received 5-year treatment with either tamoxifen (10 mg twice daily by mouth) or placebo. RESULTS: When the outcome of untreated patients in either trial was related to the stratification variables, women were found to have a disease-free survival of less than 80% through 4 years of follow-up. This percentage is apt to decrease because the probability of treatment failure increases with time. In both trials, all subsets of women benefited from M----F or tamoxifen therapy. CONCLUSIONS: The disease-free survival of all cohorts of node-negative patients with estrogen-receptor-negative or estrogen-receptor-positive tumors was poor enough to justify systemic treatment. The benefits of the therapies used are insufficient to eliminate the need for assessing putatively better regimens.