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.

Long-term tamoxifen citrate use and potential ocular toxicity.

PURPOSE: To estimate the prevalence of abnormalities in visual function and ocular structures associated with the long-term use of tamoxifen citrate. METHODS: A single-masked, cross-sectional study involving multiple community and institutional ophthalmologic departments was conducted with a volunteer sample of 303 women with breast cancer currently taking part in a randomized clinical trial to determine the efficacy of tamoxifen (20 mg/day) in preventing recurrences. Participants included women who had never been on drug (n=85); women who had taken tamoxifen for an average of 4.8 years, then been off the drug for an average of 2.7 years (n=140); and women who had been on tamoxifen continuously for an average of 7.8 years (n=78). Women were evaluated by questionnaire, psychophysical testing, and clinical examination to determine any abnormalities in visual function and the comparative prevalences of corneal, lens, retinal, and optic nerve pathology. RESULTS: There were no cases of vision-threatening ocular toxicity among the tamoxifen-treated participants. Compared with nontreated participants, the tamoxifen-treated women had no differences in the activities of daily vision, visual acuity measurements, or other tests of visual function except for color screening. Intraretinal crystals (odds ratio [OR]=3.58, P=.178) and posterior subcapsular opacities (OR=4.03, P=.034) were more frequent in the tamoxifen-treated group. CONCLUSIONS: Women should have a thorough baseline ophthalmic evaluation within the first year of initiating tamoxifen therapy and receive appropriate follow-up evaluations.

A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients undergoing preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.

Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer.

In 1985 we presented results of a randomized trial involving 1843 women followed for five years that indicated that segmental breast resection (lumpectomy) followed by breast irradiation is appropriate therapy for patients with Stage I or II breast cancer (tumor size, less than or equal to 4 cm), provided that the margins of the resected specimens are free of tumor. Women with positive axillary nodes received adjuvant chemotherapy. Lumpectomy followed by irradiation resulted in a five-year survival rate of 85 percent, as compared with 76 percent for total mastectomy, a rate of survival free of distant disease of 76 percent, as compared with 72 percent, and a disease-free survival rate of 72 percent, as compared with 66 percent. In the current study, we have extended our observations through eight years of follow-up. Ninety percent of the women treated with breast irradiation after lumpectomy remained free of ipsilateral breast tumor, as compared with 61 percent of those not treated with irradiation after lumpectomy (P less than 0.001). Among patients with positive axillary nodes, only 6 percent of those treated with radiation and adjuvant chemotherapy had a recurrence of tumor in the ipsilateral breast. Lumpectomy with or without irradiation of the breast resulted in rates of disease-free survival (58 +/- 2.6 percent), distant-disease-free survival (65 +/- 2.6 percent), and overall survival (71 +/- 2.6 percent) that were not significantly different from those observed after total mastectomy (54 +/- 2.4 percent, 62 +/- 2.3 percent, and 71 +/- 2.4 percent, respectively). There was no significant difference in the rates of distant-disease-free survival (P = 0.2) or survival (P = 0.3) among the women who underwent lumpectomy (with or without irradiation), despite the greater incidence of recurrence of tumor in the ipsilateral breast in those who received no radiation. We conclude that our observations through eight years are consistent with the findings at five years and that these new findings continue to support the use of lumpectomy in patients with Stage I or II breast cancer. We also conclude that irradiation reduces the probability of local recurrence of tumor in patients treated with lumpectomy.

Pathologic findings from the National Surgical Adjuvant Breast Project (protocol 6). II. Relation of local breast recurrence to multicentricity.

One hundred ten local breast recurrences were observed in 1108 pathologically evaluable patients enrolled in NSABP protocol 6 who were treated by lumpectomy and followed for 5 to 95 months (average, 39 months). Eighty-six percent and 95% of all local breast recurrences were noted within 4 and 5 years, respectively, following lumpectomy. Life table analysis revealed their incidence to be 24% for those not and 6% for those receiving lumpectomy and breast irradiation. One hundred four (95%) of the breast recurrences involved the mammary parenchyma and the remaining 6 (5%) involved the skin and/or nipple only. Eleven (10%) of the former were noninvasive. The most common (86%) presentation of breast recurrence appeared to be a localized mass within or close to the quadrant of the index cancer. In 14% the recurrence not only involved the same quadrant, but was more diffuse within the breast extending to remote areas as well. This type was characterized pathologically by marked intralymphatic extension as well as involvement of the overlying skin and/or nipple after the fashion of so-called inflammatory or occult inflammatory breast cancer. The recurrences noted in the skin and/or nipple only were also pathologically characterized by intralymphatic involvement at these sites in the majority of instances. These two forms of breast recurrences appear to reflect the localized growth of highly aggressive invasive breast cancers. The concordance of histologic types and grades of the index and recurrent cancers implies that such events represent growth of overlooked tumor, a deficiency attendant with lumpectomy due to the extreme multifocal nature (not multicentricity) of some breast cancers and/or inadequacies in evaluating the lines of resection of lumpectomy specimens. Sources of error in regard to this latter are identified and guidelines for the examination of such specimens, as well as the assessment of margins, are presented. The observation that local breast recurrences noted following lumpectomy occurred within or close to the same quadrant as the index cancer, despite the presence of multicentric noninvasive cancers in 10% of the patients treated by total mastectomy, minimizes the biological and clinical significance of multicentric foci of cancer present in some breast cancers. Cancer measuring greater than or equal to 2.0 cm, having high histologic and nuclear grades, or intralymphatic extension, were found to have a statistically significant association with local breast recurrence in all patients following lumpectomy. A converse relationship was noted with tubular and scar cancers of types 1 and 4.(ABSTRACT TRUNCATED AT 400 WORDS)

Pathologic findings from the National Surgical Adjuvant Breast Project (protocol 6). I. Intraductal carcinoma (DCIS).

Seventy-eight examples of intraductal carcinoma (DCIS) were identified after pathologic review of 2072 specimens obtained from National Surgical Adjuvant Breast Project protocol 6. This randomized clinical trial compares the therapeutic merit of total mastectomy (TM) with lumpectomy (L), with (LX) and without (LO) postoperative irradiation. All patients were subjected to axillary lymph node dissection. Seven (14%) of the 51 patients with DCIS treated by L exhibited breast recurrence within or close to the site of the initial lesion 4 to 53 months (average, 16 months) after L. Only 2 (7%) of these events occurred in the 29 women treated by LX, as opposed to 23% in the LO group. No pathologic features were noticed that might have been considered predictive of local breast recurrence. The three DCIS recurrences and the four invasive forms noted are considered to represent overlooked or incompletely excised foci of cancer because of the multifocality (not multicentricity) of some breast cancers. The possibility that DCIS may represent a marker of risk for the development of cancer rather than a precursor lesion per se is suggested. Despite apparent difficulties in the pathologic diagnosis of DCIS as well as uncertainty concerning its natural history, no evidence was found to indicate that it represents a more ominous disease than invasive cancer. Indeed, treatment failure occurred in only one patient treated by LX and a similar number subjected to TM (4% versus 2%). Although these observations are short term (average follow-up, 39 months), estimates of the probability of local recurrence or survival suggest that they will not be significantly altered after longer periods of surveillance. Thus, there are no compelling reasons why DCIS may not be treated in a cosmetically acceptable manner by LX. A randomized clinical trial addressing this issue is now in progress.

Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol No. 4). XI. Bilateral breast cancer.

Sixty-six confirmed instances of clinically metachronous second breast cancers were encountered over a 10-year period in 1578 women with invasive breast cancer enrolled in Protocol 4 of the National Surgical Adjuvant Breast Project (NSABP). Seven of the second cancers were in situ, yielding an incidence of 3.7% invasive and 0.5% noninvasive cancers. Except for a peak of 1.75% in the second postoperative year, the annual incidence based on patients at risk was constant and less than 1%. Ninety-three percent of the second cancers occurred within 7 years and 80% within 5 years following mastectomy for the initial primary. All of the second cancers were regarded as being primarily of mammary origin exhibiting either: (1) an in situ component; (2) dissimilar but well-recognized patterns of primary breast cancers; or (3) the appearance of scar cancer, a recently described morphologic feature characteristically observed in some primary breast cancers. A search for factors that might be predictive of bilaterality was performed. Thirty-eight pathologic and eight clinical factors were assessed, including family history. Although the latter was 1.5 to 2 times more frequent in patients with bilateral disease, this estimate was not statistically significant. On the other hand, a statistically significant association with bilateral disease was found when the initial tumor measured more than 2.0 cm, was associated with invasive cancer or proliferative fibrocystic disease, nipple involvement, absent nodal sinus histiocytosis, lobular carcinoma in situ in the vicinity of the dominant mass, or was of the lobular invasive or tubular types. However, the degree of risk of these discriminants was no greater than 2 to 3:1. Despite the clinical scrutiny imposed by the NSABP protocol second tumors measured only 1 cm less than the first, measuring on average 2.4 cm, which reflects the difficulty attendant on the clinical detection of so-called early breast cancers. Yet, no significant difference in pathologic nodal status was noted between the first and second cancers or that of patients with unilateral disease. Furthermore, there was no difference in survival rate between patients who developed a second cancer and those with unilateral disease.(ABSTRACT TRUNCATED AT 400 WORDS)

The efficacy of bone scanning in the follow-up of patients with operable breast cancer.

A considerable fraction of first metastases in breast cancer patients are found in the skeletal system. Consequently, to improve the probability of detecting bone lesions, protocols of the National Surgical Adjuvant Breast and Bowel Project (NSABP) have required radionuclide scans every six months for the first three postoperative years and yearly thereafter. The present study was conducted to evaluate the worth of 7984 bone scans performed prior to documentation of first treatment failure on 2 697 stage II (positive node) patients entered into NSABP clinical trial B-09. At the time of evaluation, there were 779 patients with a treatment failure, 163 (20.9%) of whom had their recurrence limited to bone. At most, 52 (0.6%) of the total number of screening scans were efficacious in detecting lesions in asymptomatic patients. As a result of this minimal benefit from routine scans, it was recommended that they be conducted less frequently. In presently ongoing NSABP studies, asymptomatic patients having tumors with positive axillary nodes receive scans at yearly intervals for the first three years. Future NSABP trials will require follow-up bone scans only as indicated by symptoms.

Sexual reproduction in Candida lipolytica.

Candida lipolytica is a rather common yeast isolated more frequently from substrates containing lipids or proteins, such as dairy products, than from substrates rich in sugars. This species assimilates hydrocarbons and is currently being studied for its potential to convert petroleum into yeast cells for use in feeds and foods. We have found C. lipolytica to exist in nature primarily in the heterothallic haploid state. When appropriate strains of opposite sex are mixed on a suitable sporulation medium, conjugation occurs followed by the production of ascospores. Since heterothallism permits laboratory control of hybridization, this characteristic of C. lipolytica enhances the possibility of im proving its strains for technological uses.