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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.

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Clinical studies have traditionally identified treatment-specific side effects by comparison of voiced side effects in treatment and placebo arms of a study. Highly motivated women in a clinical trial may underreport drug-induced symptoms for medications which may be considered lifesaving. Affective symptoms during treatment of early breast cancer with tamoxifen (an estradiol receptor antagonist) were reported as infrequent by the manufacturer. However, reports suggest a higher rate of depression during general use. The objective of the present study was to examine the frequency of symptoms that might be side effects of tamoxifen and to relate them to the way the women attributed such symptoms. The exploratory study involved semistructured telephone interviews of 25 women who were taking tamoxifen. Textual analysis of the information was used to examine the symptoms described by the women. They were also asked whether any symptoms were related to the medication. The symptoms and their attribution were evaluated against a background of self-perceived stress. The principal finding was a pattern of ambivalence in attributing symptoms to the drug. Of all the symptomatic changes noted, the women only attributed 51% to tamoxifen. Flushes, fatigue, and depression were reported most frequently during treatment; flushes were readily attributed to tamoxifen but depression and fatigue were attributed to another factor by half of the symptomatic women. Women who reported moderate to high levels of life stress were less likely to attribute symptoms to drug therapy. The results suggest that women taking tamoxifen may not attribute known drug side effects to use of the medication.

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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.

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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.

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BACKGROUND: Epidemiological studies have demonstrated that obesity and low oestrogen receptor level adversely affect survival from breast cancer. Few studies have examined the joint effects of these variables. METHODS: A cohort study was conducted in which 1169 breast cancer patients from the Northern Alberta Breast Cancer Registry were followed for an average of 4.4 years. A number of variables related to breast cancer incidence and prognosis were studied. Body mass index (BMI) was used as a proxy measure of obesity. RESULTS: A Cox regression analysis resulted in a final model with terms for size of tumour, number of positive axillary nodes, oestrogen receptor level, BMI, and age at diagnosis, plus an interaction term for node status and BMI. Having relatively less oestrogen receptor increased the hazard ratio by 1.8 (95% CI: 1.4-2.3); for woman with no positive nodes, being in the highest quartile of BMI increased the hazard ratio by 2.5 (95% CI: 1.2-5.2) compared to the lowest quartile. CONCLUSIONS: BMI and oestrogen receptor level independently influence survival from breast cancer, but BMI affects survival only in patients with no positive axillary nodes.

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Drawing upon the comprehensive population-based Northern Alberta Breast Cancer Registry containing 704 patients with histologically negative axillary lymph nodes who have been followed for 5-16 years, we have undertaken a retrospective case-control study to evaluate the utility of genomic amplification of specific protooncogenes [c-erbB-2 (nee HER-2/neu), c-erbA, c-myc, int-2, and hst-1] as predictive indicators of clinical outcome in node-negative disease. To this end, 115 women with node-negative breast cancer who had recurred at any time up to 16 years posttreatment (cases) were matched pairwise for appropriate clinicopathological variables (size of primary tumor, menopausal state, estrogen receptor status, anniversary year of treatment, and patient age) with a second group of 115 women (controls) selected from a cohort of 502 node-negative patients who had not relapsed during long-term follow-up. Tumor DNA extracted from archival formalin-fixed, paraffin-embedded tissue blocks were analyzed for protooncogene copy number by slot-blot hybridization. Taking a gene copy number of 3 as the cutoff, 27 of the 230 tumor samples examined contained from 3- to 22-fold elevation in c-erbB-2 genomic equivalents. Twenty-one of the 27 tumors amplified for c-erbB-2 were derived from cases and 6 from controls, signifying that 18% of the node-negative patients who had relapsed harbored excessive copies of the protooncogene in their malignant tissue compared to only 5% for the patients who had remained in remission. Accordingly, the occurrence of amplification of c-erbB-2 proved to be a statistically significant predictor of poor prognosis, especially disease-free interval (P = 0.006). Moreover, this genetic alteration appeared to be independent of and to have greater predictive power than most commonly used prognostic factors. Our findings also indicated that as a clinical test, measurement of c-erbB-2 amplification suffers from low sensitivity; however, when greater than 6 gene copies are present, the test has a positive predictive value for recurrence of 70%. Concurrent analysis of tumor DNA blots with probes for the other four protooncogenes examined revealed that their amplification, which others have reported to arise often, especially in node-positive disease, was seldom found even in our high-risk case group (2-3%). In short, our data strongly suggest that amplification of c-erbB-2 may contribute to the pathogenesis of some forms of node-negative breast cancer and thus may serve as a useful genetic marker to identify a subset of high-risk patients.

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The entire experience of in situ breast cancer in Alberta from 1953 to 1984 was examined. Of 243 patients coded, 226 were available for review by a panel of three pathologists. In 149 cases the diagnosis of in situ disease was confirmed. One hundred and eight patients had 109 ductal carcinomas in situ, 38 patients had lobular carcinomas in situ, with 3 patients having both. A multitude of treatments was used, ranging from local excision to radical mastectomy. Survival at a mean of 6 years follow-up was equal in all groups, with only two patients with a confirmed diagnosis of ductal carcinoma in situ dying from clinically suspected systemic disease. In patients treated by local excision, ipsilateral cancers were seen in 12% of ductal carcinoma in situ patients who had local excision and 13% of patients with lobular carcinoma in situ. Contralateral metachronous invasive cancers were seen in 6% of ductal carcinoma in situ patients and 3% of lobular carcinoma in situ patients. No lymph node involvement was seen in any of these patients, either with prophylactic dissection or in follow-up. The conclusion reached was that both in situ lesions are similar in their clinical course. Lymph node dissection is not necessary. Pathologic review is critical for accurate studies, with a change in diagnosis of 36% of diagnoses. Treatment does not appear to affect prognosis. The most appropriate treatment needs to be determined in prospective randomized trials.

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1,121 women in northern Alberta diagnosed as having breast cancer between 1971-74 were followed for 10 years. Risk factors for breast cancer were studied with respect to their possible influence on survival by comparing survival curves, using both Logrank and Cox's regression model, and controlling for intercurrent death, stage and axillary node status. A complex interaction was found between age and menopausal status and survival rates. Premenopausal women aged 45-55 had a better survival rate than postmenopausal women of the same age. However, one subgroup of premenopausal women aged 35-39 had a significantly worse prognosis than those aged 40-44 as did a group of post menopausal women aged 70-74. No cause was found other than the effect of age. There was a significant trend to worsening survival with heavier weight at time of diagnosis and with breast feeding. Parity of five or more and family history of breast cancer were less consistently associated with worse survival. Oral contraceptive use was only associated with worsened prognosis significantly when stage was controlled for; there was no overall effect. Age at menarche and age at first birth did not influence prognosis. Theories to explain the findings are discussed.

PIP: Risk factors associated with 10-year survival with breast cancer were analyzed using survival curves, with both Log rank and Cox's regression models, controlling for intercurrent death, stage and axillary node status. 1121 women from northern Alberta diagnoses with breast cancer from 1971-1974 were followed for 10 years, with history and physical exams done on 92% of patients by 1 or 2 persons. At 10 years only 41 were lost to follow-up, 41% were alive and well, 10% were alive with metastatic disease, 34% were dead from breast cancer and 11% were dead from other causes. Premenopausal women aged 45-55 had better survival than postmenopausal women of the same age. Premenopausal women aged 35- 59 had a significantly worse prognosis than women aged 40-44. Women aged 70-74 also had a poor prognosis. Worse survival was associated with heavier weight at diagnosis. Women with history of breast feeding for 2 weeks or more had a 51% survival rate, less than the 60% for those who did not breast feed. Parity of 5 or higher and family history of breast cancer were less closely related to worse survival. Oral contraceptive use 1 month or more had no overall association, but was associated with worse prognosis when stage was controlled. Age at menarche and age at 1st birth did not influence prognosis.

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The clinical response to first systemic therapy of 381 patients with metastatic breast cancer was assessed; the influence of the category of this first response on eventual survival from diagnosis of first distant metastasis was analyzed. Survival from diagnosis of first distant metastasis was found to be similar whether the patient had a complete response, a partial response, or stable disease; only when progressive disease occurred with first systemic treatment was survival significantly shortened. This similarity in survival whatever the category of response from diagnosis of first distant metastases was found whether the patient received chemotherapy or hormone therapy as first systemic treatment, and whether the patient was premenopausal or postmenopausal; there was some suggestion on analysis of premenopausal patients treated with hormone therapy as first systemic therapy that a complete response conferred a survival advantage, but the numbers were small in this group. When complete responders to first systemic therapy as well as any other subsequent systemic therapy were analyzed for survival from diagnosis of first distant metastasis, again, no survival advantage could be found compared to the other response categories, but the complete response rate was low owing to the unselected nature of this group of study patients. It is concluded that the categories of complete, partial, or stable response to therapy have no great significance in terms of survival; the category of progressive disease to first systemic therapy is, however, associated with a shorter survival in all the analyses performed. We suggest that assessment of a treatment's worth should be based as much on the patient's subjective feeling of well-being as on the magnitude of the tumor response, since with currently available therapies, provided some form of response is obtained, the magnitude of the response does not appear to translate into any major survival advantage. This study points up the disparity between research-oriented criteria of response (survival, response rate, and its magnitude) and patient care criteria of response (survival and quality of life).

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Of 2231 women with stage I, II or III breast cancer who were registered and seen between 1971 and 1979 and followed to the end of 1981, 48 (2.2%) had synchronous and 58 (2.6%) asynchronous bilateral breast cancer. The unadjusted incidence rate for a second breast cancer was 6.4/1000 breast-years at risk, compared with a rate of 0.70 for the risk of a first breast cancer in women. When calculated from the date of diagnosis of the first breast cancer the survival rate was better for the group with asynchronous disease than for the group with synchronous disease or for a group with unilateral disease, but when calculated from the date of diagnosis of the second cancer the rate was the same in all three groups. Comparison of known risk factors showed a significant association between the development of bilateral cancer and a later age at the birth of the first child and a longer interval between menarche and that birth. There was a trend towards greater age and more stage III cancer in the group with synchronous disease. There was no correlation between receiving radiotherapy for the first breast cancer and development of the second cancer. Annual mammography and clinical examination of asymptomatic women at a cancer centre resulted in the detection of a significantly higher proportion of minimal breast cancers in the second breast compared with the first. Such screening practices should be even more valuable in the earlier detection of unilateral breast cancer in asymptomatic women who have not had breast cancer.

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A log-linear model was used to separate age, secular, and cohort trends in the incidence of cancer of the breast, ovary, corpus uteri, cervix uteri, vagina, and vulva in female residents in Alberta over the period 1953 to 1977. The age trends are similar for each cancer site increasing sharply in the premenopausal period and then leveling off. In the case of breast cancer, a point of inflection at the menopause (Clemmesen's hook) persists. A gradually increasing secular trend in incidence was evident for all sites except cervix uteri, the incidence of which declined after 1960. Cyclical cohort trends were found for cancers of the breast, ovary, and corpus uteri, inversely correlated with early fertility. The cohort trends for cervix uteri, vagina, and vulva increased sharply for cohorts born after 1940.

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A population-based incident case-control study of breast cancer in Northern Alberta, Canada, provided an opportunity to evaluate interactions between the occurrence of benign breast disease (BBD) and other potential risk factors. Overall there was a 2-fold excess risk of breast cancer among women with BBD. This excess persisted regardless of the number of years from first biopsy for BBD to diagnosis of breast cancer, suggesting a permanent alternation in risk with BBD. Significant variations of the BBD--breast cancer association were noted with several factors. The excess risk of breast cancer among women with BBD was enhanced by having a later age at menarche, a later age at first birth, or lower parity. The usual protective effect of late age at menarche was seen only among women without BBD, and was supplanted by a 4-fold elevated risk among women with BBD. The deleterious effects of later age at first birth and nulliparity were greater among women with BBD. These patterns generally support the notion that hormonal factors mediate the relation between BBD and the development of breast cancer.

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A population-based case-control study involving interviews with 577 female breast cancer patients and 826 controls in northern Alberta. Canada, revealed that some determinants of breast cancer varied according to age. Among women under age 45, risk factors included a younger age at menarche, late age at last birth, high parity, and recent use of oral contraceptives. At older ages risk was related to natural as opposed to surgical menopause, late age at first birth, low parity, late age at natural menopause, and tonsillectomy. At all ages there was an increased risk of breast cancer associated with difficulty in conceiving, benign breast disease, not having breast fed, and a history of breast cancer among mothers or sisters. For some variables the age differences were pronounced; the combination of low parity and late age at first birth was associated with a sevenfold increase in breast cancer risk at risk at ages 55-80 but a slight decrease at ages under 45. The effect of tonsillectomy steadily increased with age and represents a new lead, but certain features of the data suggest that the link to oral contraceptives among among younger women and the inverse relation to breast feeding at all ages may not be causal. Even though design limitations (cases interviewed in a different setting from controls) appeared not to influence conclusions, the results may have been subjected to interview bias and thus should be interpreted cautiously.

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As part of a case-control study in northern Alberta, Canada, 577 women aged 30-80 with breast cancer diagnosed during 1976-77 and a population-based age-stratified random sample of 826 disease-free female controls were questioned about certain aspects of their diet. Computing relative risks (RRs) by tertiles, significant increasing trends were found with more frequent consumption of beef (RRs of 1.0, 2.3, 1.5; test for trends, p less than 0.001), pork (RRs of 1.0, 1.6, 2.2; test for trend, p less than 0.001), and sweet desserts (RRs of 1.0, 1.3, 1.5; test for trend, p = 0.01). Elevated risks were also noted for use of butter at the table and for frying with butter or margarine, as opposed to vegetable oils. The association of total beef and pork consumption with breast cancer was not materially affected by controlling for age at first birth, family history of breast cancer, previous benign breast biopsy or socioeconomic status. Nor was the association reduced by controlling for ages of menarche and menopause, even though within the control series the intake of beef and pork reported in adult life was higher among those with a lower age at menarche or a older age at natural menopause.

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Reproductive events and family history as risk factors for breast cancer in northern Alberta were investigated with the use of data from a computerized population-based registry. Women aged 30 to 79 years attending diagnostic breast clinics at the Cross Cancer Institute from 1971 through 1975 constituted the two study groups; 1232 women had diagnosed breast cancer (malignant disease group) and 602 women were clinically free of all types of breast disease (control group). An increased relative risk of breast cancer was found in women with a family history of breast cancer, those who gave birth to their first term infant at age 30 years or older, those in whom more than 15 years elapsed between menarche and that birth, and those with a late natural menopause. There was a decreased risk, relative to nulliparity, in the postmenopausal women who first gave birth to a term infant 5 years or less after menarche. Artificial menopause (bilateral oophorectomy), parity and age at menarche had no apparent effect on the risk. The pattern of risk factors in northern Alberta differed from that reported for other geographic areas, including other provinces of Canada, thus emphasizing the need for local studies in the planning of screening programs.

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In order to assess the impact of modern combination chemotherapy on overall survival of metastatic breast cancer patients, we retrospectively analysed survival data of those patients who presented with breast cancer and developed metastases at our clinic from 1971-78 inclusive. Our results indicate a trend towards improved survival from onset of first distant metastasis after 1975. Assessment of survival by treatment modality revealed significantly longer survival from first metastasis for those patients receiving predominantly endocrine treatment compared to chemotherapy, median survival being 32.5 versus 23 months for endocrine therapy and chemotherapy respectively. Patients receiving adriamycin in combination with other drugs, had longer survival from first metastasis than those patients receiving chemotherapy without adriamycin (median survival being 25 versus 18.5 months respectively). These differences are most probably due to patient selection. On the basis of these results it would appear that chemotherapy may be improving short-term survival in some patients, but is making no major impact on long-term survival.

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