Breast cancer after mantle irradiation for Hodgkin's disease: correlation of clinical, pathologic, and molecular features including loss of heterozygosity at BRCA1 and BRCA2.

PURPOSE: Hodgkin's disease patients who receive mantle irradiation have an age-dependent increased risk of developing breast cancer. To determine if genetic factors predispose these patients to develop breast cancer, we evaluated breast cancer specimens for loss of heterozygosity (LOH) at regions where BRCA1 and BRCA2, two breast cancer tumor suppressor genes, are located. We also evaluated whether breast cancers in patients who were previously treated with radiation have a more aggressive phenotype, and whether the clinical course differed from a sporadic group of breast cancer patients. METHODS AND MATERIALS: All females with Hodgkin's disease who were subsequently diagnosed with breast cancer and for whom tissue blocks were available were included. Using a case-control design, case patients (previously treated with radiation therapy) were matched with sporadic control breast cancer patients for age, breast cancer stage, and date of breast cancer diagnosis. After microdissection of tumor and normal tissue from paraffin-embedded tissue blocks, DNA was extracted and samples were examined for LOH at chromosomal segments encompassing BRCA1 and BRCA2. Breast cancer specimens were also evaluated in a blinded fashion for tumor grade and immunoreactivity to estrogen and progesterone receptors, p53, her2-neu, and topoisomerase II alpha. Comparisons were made between the case and control populations using chi2 analysis, and a paired Student's t test. Survival differences were evaluated using a log-rank test. RESULTS: From January 1960 to December 1983, 917 patients were diagnosed with Hodgkin's disease. Twelve patients were subsequently diagnosed with breast cancer and tissue blocks were available on 10 cases. No statistical difference was observed between the case and control populations for LOH at BRCA1 or BRCA2. In the Hodgkin's disease group, LOH was observed in 30% of tumors at BRCA1 and 10% of tumors at BRCA2 vs. 10% and 0% of tumors in the control group at BRCA1 and BRCA2, respectively. Breast tumors from patients who received radiation therapy for Hodgkin's disease displayed greater nuclear pleomorphism (p < 0.02), and an increase in topoisomerase II alpha expression (p < 0.05) vs. the control population. Five of 10 patients were pregnant at the time of their Hodgkin's treatment, and those patients had a shorter time interval to the development of breast cancer compared with the patients who were not pregnant (12.4 years compared with 18.6 years). There was no significant difference in disease-free survival; however, overall survival was inferior in the population previously treated with radiation therapy for Hodgkin's disease (p = 0.01). 80% of patients with a previous Hodgkin's diagnosis died of breast cancer or treatment related effects vs. 30% in the control group. CONCLUSION: We were unable to find statistical evidence for LOH at BRCA1 and BRCA2 in breast cancers from patients previously irradiated for Hodgkin's disease. Breast cancer diagnosed after mantle irradiation may be more biologically aggressive based on the greater nuclear pleomorphism and increase in topoisomerase II alpha staining. This did not translate into a statistical difference in breast cancer disease-free survival; however, overall survival was significantly inferior in the Hodgkin's disease patients.

Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations.

BACKGROUND AND PURPOSE: The purpose of this study is to evaluate overall survival in BRCA1 or BRCA2 breast cancer patients, describe presenting stage, review histologic findings and evaluate response to radiotherapy. MATERIALS AND METHODS: A retrospective study was performed evaluating breast cancer patients with known mutations of BRCA1 or BRCA2. Patients from 12 different pedigrees were cross-referenced with the Utah Cancer Registry (UCR), histologic findings were verified and radiotherapy records were reviewed for acute response to treatment. Actuarial survival calculations were performed and patients were matched for age, date of diagnosis and tumor size. RESULTS: Thirty breast cancer patients with BRCA1 mutations were found to have 34 breast cancers (four had bilateral metachronous lesions) and 20 breast cancer patients with BRCA2 mutations were found to have 22 breast cancers (two had bilateral metachronous disease). The median age at diagnosis was 49 years (range 21-77 years) and 42 years (range 23-83 years), respectively, for BRCA1 and BRCA2 patients. Unusual histologic types of breast cancers were represented with 7% (4/56) medullary and 5% (3/56) lobular carcinomas. Complete staging was possible for 63% (35/56) of cancers. Stages I, II, III and IV represented 26, 63, 6 and 6% of cancers, respectively. The most severe radiation reaction was moist desquamation which was self-limiting and developed in 29% (6/21) of irradiated patients. The mean follow-up was 9.8 and 7.5 years for BRCA1 and BRCA2 cancers, respectively. Kaplan-Meier survival analysis demonstrated 5-year survival values of 75% for BRCA1 patients, 73% for BRCA2 patients, 70% for matched controls and 69% for UCR controls. No statistically significant differences were evident between the groups at 5 or 10 years. CONCLUSIONS: Despite their younger age at presentation, breast cancer patients harboring BRCAI or BRCA2 mutations present at a similar stage, display a normal acute reaction to radiotherapy and have a similar prognosis when compared with sporadic breast cancer patients.

Treatment of adenocarcinoma of the stomach with resection, intraoperative radiotherapy, and adjuvant external beam radiation: a phase II study from Radiation Therapy Oncology Group 85-04.

BACKGROUND: Fewer than 10% of patients presenting with adenocarcinoma of the stomach in the United States can expect to be cured. These discouraging results have led to trials of various adjuvant therapies. Some studies suggest a role for radiation in improving regional control. Radiation doses, however, are limited by the tolerance of abdominal organs. METHODS: Between 1985 and 1989, the Radiation Therapy Oncology Group conducted a phase II study to determine the feasibility of using intraoperative radiotherapy (IORT) in the treatment of adenocarcinoma of the stomach. Forty-three patients were entered into the study. Patients underwent maximal surgical resection (subtotal or total gastrectomy and regional node dissection) and IORT doses of 12.5-16.5 Gy were delivered in 27 patients. Adjuvant external beam radiation was given to 23 of the 27 patients with total doses ranging from 24 to 50 Gy. RESULTS: Two-year actuarial survival in the 27 patients receiving IORT was 47% and median survival was 19.3 months. Disease-free survival was 27%. Fifteen percent failed locally only, 26% with distant metastases only and 22% with both. Acute postoperative complications occurred in 14% with one fatality. Severe late complications occurred in 7% with one fatality. CONCLUSIONS: Intraoperative radiotherapy combined with surgical resection and postoperative radiotherapy appears to be feasible without excessive morbidity in a multiinstitutional study. Its ultimate value requires further study.

Late effects following central nervous system radiation in a pediatric population.

Between 1970 and 1986, 120 children with central nervous system malignancy were treated with radiation therapy. These included 44 low-grade astrocytomas, 11 high grade astrocytomas, 32 medulloblastomas, 15 ependymomas/ependymoblastomas, 3 primitive neuroectodermal tumors and 8 pineal tumors. Seven children were treated without biopsy. Fifty-one treated children were evaluated for the effects of therapy on growth, endocrine function, IQ and hair regrowth. Mean height was 1.5 standard deviations below the mean height for the patient's age at study (range 0-5.7). Height was significantly less in patients receiving radiation to the pituitary and those with somatomedin-C deficiency. Height was also decreased with whole CNS radiation and spine dose > 20 Gy but not to a significant degree. Pituitary radiation in any dose increased the chance of endocrine deficiency (p = 0.004) and 21 of 51 patients had somatomedin-C deficiency. Mean IQ was 92.7 (+/- 18.8), with a slight trend toward decreased IQ with increasing whole brain dose of radiation. Hair regrowth was complete in 20 of 46 evaluated patients, diminished regrowth occurring with increasing volume and dose of radiation. No difference in the measured late effects could be detected with respect to age at treatment, sex, histology or location of tumor.

Three-dimensional viewing of and dosimetric calculations in Au-198 implants of the prostate.

A three-dimensional system for dosimetric calculation of radiation from interstitial brachytherapeutic implants was developed and was compared with conventional dosimetry performed with a commercial two-dimensional system. Software programs written for this study enabled the authors to place radioactive sources in the correct reconstructed anatomic locations, compute the isodose distribution around these sources, and display the isodose curves in their correct relationship to anatomic structures. Eight radiation oncologists evaluated the usefulness of both systems. Verification studies in phantoms and in 20 patients with gold-198 implants in the prostate gland showed that the experimental system was very accurate in volume reconstruction, seed localization, isodose distribution, point-dose calculation, and computation of dose-volume histograms. Although the dose depictions in the two systems matched almost exactly, statistically significant differences existed in interpretation of the dosimetric data generated by both systems. For example, the oncologists consistently believed that the dose to the prostate was lower when the three-dimensional system was used (P less than or equal to .0001).

Utility of surgical margins in the radiotherapeutic management of soft tissue sarcomas.

Seventy-four adult patients with localized soft tissue sarcomas were treated with radiation therapy following surgery between 1965 and 1988. Fifty-three were treated after the first excision of their tumor with 6 (11.3%) local recurrences. Twenty-one received radiation after excision of recurrent disease with 11 (52.4%) local failures (P less than .0005). Metastatic disease occurred in 14 (26.4%) of the primary tumors and 8 (38.1%) with multiple previous excisions (P less than .48). Of those patients treated for primary sarcoma, there were no local failures with pathologically wide margins or if a single margin was microscopically positive. Local failure occurred in 4 of 26 (15.4%) if the tumor was merely enucleated and in 2 of 11 (18.2%) who had grossly positive surgical margins (P not significant). Local failure was also more common in truncal locations (33.3%) as compared with extremity locations (8.7%, P = .1359). Additional factors analyzed which adversely affected prognosis included tumor grade, stage, and inadequate radiation dose.

Morbidity and mortality associated with intraoperative radiotherapy.

From May 1984 through July 1988, 67 patients have been treated with intraoperative radiation therapy (IORT) at LDS Hospital. We conducted a detailed evaluation of the morbidity and mortality related to our intraoperative experience. Major complications were classified as those requiring reoperation or resulting in death. Minor complications included all others that could not be attributed to tumor growth or recurrence. Of twelve major complications, three resulted in death. Nonfatal complications included anastomotic leak (5), wound dehiscence (1), gastric outlet obstruction (1), and bowel obstruction (1). When compared with historical controls undergoing comparable surgery at this institution prior to the availability of IORT, complication rates were similar. We feel in our institution, intraoperative radiotherapy has not added to morbidity of aggressive abdominal surgery.