Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol.

INTRODUCTION: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer. METHODS: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events. ETHICS AND DISSEMINATION: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. TRIAL REGISTRATION NUMBER: NCT02603341.

Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer.

BACKGROUND: Although BRCA1 has been extensively studied for its role as a tumour-suppressor protein, the role of BRCA1 subcellular localisation in oncogenesis and tumour progression has remained unclear. This study explores the impact of BRCA1 mislocalisation on clinical outcomes in breast cancer. METHODS: Tissue microarrays assembled from a cohort of patients with all stages of breast cancer were analysed for BRCA1 localisation and correlated with patient survival. Tissue microarrays of patients who had breast cancer that had metastasised to the lung were assembled from an independent cohort of patients. These were analysed for BRCA1 subcellular expression. In vitro studies using cultured human breast cancer cells were conducted to examine the effect of cytosolic BRCA1 on cell migration and efficiency of invasion. RESULTS: An inverse association was found between cytosolic BRCA1 expression and metastasis-free survival in patients aged >40 years. Further analysis of BRCA1 subcellular expression in a cohort of breast cancer patients with metastatic disease revealed that the cytosolic BRCA1 content of breast tumours that had metastasised to the lung was 36.0% (95% CI=(31.7%, 40.3%), which was markedly higher than what is reported in the literature (8.2-14.8%). Intriguingly, these lung metastases and their corresponding primary breast tumours demonstrated similarly high cytosolic BRCA1 distributions in both paired and unpaired analyses. Finally, in vitro studies using human breast cancer cells demonstrated that genetically induced BRCA1 cytosolic sequestration (achieved using the cytosol-sequestering BRCA1 5382insC mutation) increased cell invasion efficiency. CONCLUSIONS: Results from this study suggest a model where BRCA1 cytosolic mislocalisation promotes breast cancer metastasis, making it a potential biomarker of metastatic disease.

Basal subtype, as approximated by triple-negative phenotype, is associated with locoregional recurrence in a case-control study of women with 0-3 positive lymph nodes after mastectomy.

PURPOSE: Basal subtype, as approximated by the triple-negative phenotype (ER-PR-Her2-), has correlated with higher LRR in recent studies. Indications for postmastectomy RT (PMRT) in women with 0-3 positive lymph nodes remain unclear. We evaluated the importance of biologic subtype in a cohort of women with LRR after mastectomy. METHODS: We identified 22 women with 0-3 positive lymph nodes at our institution who were initially treated with mastectomy (without post-mastectomy radiation), suffered LRRs, and had paraffin-embedded tissue blocks from the primary mastectomy specimen available for staining. None of these women received PMRT. We case-control matched these to 29 women with 0-3 positive nodes who had mastectomy (no PMRT) and remained without evidence of disease at last follow-up and had available primary specimens for processing. We matched controls for age (±3 years) and follow-up duration (<5 year vs. more). Paraffin-embedded specimens were used to construct a triple-redundant tissue microarray. We used conditional logistic regressions to study the association between each predictor and LRR. Results were summarized based on odds ratio (OR). RESULTS: On univariate analysis, ER+, PR+, or the combination was strongly associated with lower odds of LRR. Basal subtype, as approximated by ER-PR-Her2- (TN), was associated with higher LRR (OR 8.5, p = 0.048). Use of chemotherapy also was associated with lower LRR (OR 0.126, p = 0.0073). CONCLUSIONS: Our data are concordant with reports from others demonstrating that TN phenotype is associated with higher LRR and can be considered along with other predictors of LRR when selecting women for PMRT.

Dosimetric feasibility and acute toxicity in a prospective trial of ultrashort-course accelerated partial breast irradiation (APBI) using a multi-lumen balloon brachytherapy device.

BACKGROUND: Shorter courses of APBI, including single-fraction intraoperative therapy, are under active investigation. We designed a prospective trial to identify and address the potential radiobiological and logistical shortcomings of single-fraction APBI. METHODS: We designed a single-arm, multi-institutional, prospective phase II trial that sequentially treats 3 cohorts of women (each n = 30) with 3 progressively hypofractionated schedules. Eligible women were age ≥50 years with unifocal invasive or in situ tumors ≤3.0 cm, excised with negative margins, and with negative lymph nodes and positive hormone receptors. We defined strict dosimetric criteria for appropriateness. RESULTS: A total of 30 patients were enrolled at the 7 Gy × 4 fractions dose-level and followed for 6 months. The median skin dose as a percent of prescription dose (PD) was 84 % (40-100), and the median rib dose was 71 % (16-119). Also, 95 % of the PTV_eval received a median of 95 % of PD (range 85-103). The V150 (range 14-48 cc) and V200 (range 0-29 cc) criteria were met in all cases. One breast infection occurred and was treated; 2 cases of symptomatic fat necrosis and 2 cases of symptomatic seromas occurred. CONCLUSION: Short-course APBI is dosimetrically feasible using the Contura MLB and appears to be tolerable in terms of acute toxicities. Our approach is based on well-defined radiobiological parameters and allows for an abbreviated course of treatment that is guided by full pathological review and the ability to objectively achieve and validate acceptable dosimetric criteria in each case. We have opened enrollment to the next schedule of 8.25 Gy for 3 fractions.

Six-year analysis of treatment-related toxicities in patients treated with accelerated partial breast irradiation on the American Society of Breast Surgeons MammoSite Breast Brachytherapy registry trial.

BACKGROUND: The American Society of Breast Surgeons (ASBrS) enrolled women in a registry trial to prospectively study patients treated with the MammoSite RTS device. This report presents 6-year data on treatment-related toxicities from the trial. METHODS: A total of 1449 primary early-stage breast cancers were treated with accelerated partial breast irradiation (APBI) using the MammoSite device (34 Gy in 10 fractions) in 1440 women. Of these, 1255 case (87%) had invasive breast cancer (IBC) (median size = 10 mm) and 194 cases (13%) had ductal carcinoma in situ (DCIS) (median size = 8 mm). Median follow-up was 59 months. Fisher exact test was performed to correlate categorical covariates with toxicity. RESULTS: Breast seromas were reported in 28% of cases (35.5% with open cavity and 21.7% with closed cavity placement). Also, 13% of all treated breasts developed symptomatic seromas, and 77% of these seromas developed during the 1st year after treatment. There were 172 cases (11.9%) that required drainage to correct. Use of chemotherapy and balloon fill >50 cc were associated with the development of symptomatic seromas. Also, 2.3% of patients developed fat necrosis (FN). The incidence of FN during years 1 and 2 were 0.9% and 0.8%, respectively. Seroma formation, use of hormonal therapy, breast infection, and A/B cup size were associated with fat necrosis. There were 138 infections (9.5%) recorded; 98% occurred during the 1st year after treatment. Chemotherapy and seroma formation were associated with the development of infections. CONCLUSIONS: Treatment-related toxicities 6 years after treatment with APBI using the MammoSite device are similar to those reported with other forms of APBI with similar follow-up.

Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups.

BACKGROUND: Despite significant differences in age of onset and incidence of breast cancer between Caucasian (CA), African-American (AA) and Korean (KO) women, little is known about differences in BRCA1/2 mutations in these populations. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations and the association between BRCA1/2 mutation status and secondary malignancies among young women with breast cancer in these three racially diverse groups. METHODS: Patients presenting to our breast cancer follow-up clinics selected solely on having a known breast cancer diagnosis at a young age (YBC defined as age <45 years at diagnosis) were invited to participate in this study. A total of 333 eligible women, 166 CA, 66 AA and 101 KO underwent complete sequencing of BRCA1/2 genes. Family history (FH) was classified as negative, moderate or strong. BRCA1/2 status was classified as wild type (WT), variant of uncertain significance (VUS) or deleterious (DEL). RESULTS: DEL across these three racially diverse populations of YBC were nearly identical: CA 17%, AA 14% and KO 14%. The type of DEL differed with AA having more frequent mutations in BRCA2, compared with CA and KO. VUS were predominantly in BRCA2 and AA had markedly higher frequency of VUS (38%) compared with CA (10%) and KO (12%). At 10-year follow-up from the time of initial diagnosis of breast cancer, the risk of secondary malignancies was similar among WT (14%) and VUS (16%), but markedly higher among DEL (39%). CONCLUSIONS: In these YBC, the frequency of DEL in BRCA1/2 is remarkably similar among the racially diverse groups at 14%-17%. VUS is more common in AA, but aligns closely with WT in risk of second cancers, age of onset and FH.

Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women.

PURPOSE: To evaluate the frequency and distribution of BRCA1 and BRCA2 mutations in a cohort of young women with breast cancer and to compare the distribution of mutations as a function of race. METHODS: After IRB approved informed consent, 170 white women and 30 African American women with known breast cancer diagnosed at a young age (45 years or less) underwent complete sequencing of the BRCA1 and BRCA2 genes. Each cohort represented approximately 40% of women of the same ethnic background aged 45 years or younger in a breast cancer database. RESULTS: Of the 200 patients tested, 131 (65%) had wild type mutations, 34 (17%) had deleterious mutations, and 35 (18%) had variants of uncertain significance. There were no significant differences between the white and African American cohorts regarding the percentage of deleterious mutations (17% v 17%). However, most African American patients had mutations in BRCA2 (4/5, 80%), while most mutations in the white cohort were in BRCA1 (20/29, 69%). In addition, 46% of the African American women had variants of uncertain significance, compared to only 12% of the white cohort. CONCLUSIONS: Young African American women with breast cancer have a similar frequency of deleterious mutations as white women, but have a significantly higher frequency of variants of uncertain significance. Review of these variants revealed that the majority were unlikely to be associated with disease risk or were likely to be polymorphisms. The implications for genetic testing and counselling in young women with breast cancer are discussed.

Prognostic significance of p16 protein levels in oropharyngeal squamous cell cancer.

PURPOSE: Functional inactivation of p16 is an early and frequent event in head and neck squamous cell cancers. In this study, we sought to determine whether p16 expression is of prognostic importance in oropharyngeal squamous cell carcinoma. EXPERIMENTAL DESIGN: p16 protein expression was evaluated by immunohistochemistry in a tissue microarray composed of 123 oropharyngeal squamous cell cancers with a mean patient follow-up time of 33 months. RESULTS: p16 overexpression was associated with more advanced Tumor-Node-Metastasis stage and higher histologic grade. Despite this association with unfavorable features, p16 overexpression was associated with decreased 5-year local recurrence rates (11 versus 53%) and increased 5-year disease-free survival (62 versus 19%) and overall survival (60 versus 21%). In multivariate analysis, p16 expression status remained an independent prognostic factor for local recurrence, disease-free survival, and overall survival. CONCLUSIONS: In patients with oropharyngeal squamous cell carcinoma, overexpression of p16 as determined by immunohistochemistry is associated with significantly improved prognosis and lower local recurrence rates.

Cisplatin, fluorouracil, and leucovorin induction chemotherapy followed by concurrent cisplatin chemoradiotherapy for organ preservation and cure in patients with advanced head and neck cancer: long-term follow-up.

PURPOSE: The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. PATIENTS AND METHODS: Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy. RESULTS: Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. CONCLUSION: Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.

Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Molecular marker expression in oral and oropharyngeal squamous cell carcinoma.

OBJECTIVE: To determine the relative prognostic value of p53, cyclin D1, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) expression in patients with oral and oropharyngeal squamous cell carcinoma. DESIGN: Retrospective cohort study. PATIENTS: Fifty-six patients with oral and oropharyngeal squamous cell carcinoma referred to the Department of Therapeutic Radiology at Yale-New Haven Hospital (Conn) between 1981 and 1992 who were treated with gross total surgical resection and postoperative external beam radiotherapy. RESULTS: Archival tumor tissue was stained with monoclonal antibodies directed against these 4 oncoproteins and scored for staining intensity and percent distribution by a pathologist blinded to the patients' clinical outcomes. Frequency of marker expression was 48% for p53, 20% for cyclin D1, 64% for EGFR, and 41% for VEGF. In multivariate analysis, EGFR positivity was protective against locoregional relapse (relative risk [RR], 0.27; 95% confidence interval [CI], 0.11-0.66; P =.002). In contrast, advanced N stage predicted poor locoregional relapse-free survival (RR, 1.94; 95% CI, 1.03-3.66; P =.04). Predictors of poor overall survival in multivariate analysis included VEGF positivity (RR, 3.53; 95% CI, 1.75-7.13; P<.001) and black race (RR, 2.48; 95% CI, 1.05-5.85; P =.04). Cyclin D1 and p53 expression were not significantly associated with prognosis in this cohort. CONCLUSIONS: In oral and oropharyngeal squamous cell carcinoma treated with surgery and postoperative radiotherapy, VEGF and EGFR expression may influence clinical outcome. If confirmed, these results have potential implications for the determination of patient prognosis and the development of biologically based pharmacotherapies.

Adenoid cystic carcinoma: a retrospective clinical review.

Adenoid cystic carcinoma (ACC) are uncommon tumors, representing about 10% to 15% of head and neck tumors. We compare the survival and control rates at our institution with those reported in the literature, and examine putative predictors of outcome. All patients registered with the tumor registry as having had ACC were identified. Demographic and survival variables were retrieved from the database. Additionally, a chart review of all patients was done to obtain specific information. Minor gland tumors were staged using the American Joint Committee on Cancer's criteria for squamous cell carcinomas in identical sites. Histopathologic variables retrieved included grade of the tumor, margins, and perineural invasion. Treatment modalities, field sizes, and radiation doses were recorded in applicable cases. An effort to retrieve archival tumor specimens for immunohistochemical analysis was undertaken. A total of 69 patients were treated for ACC from 1955 to 1999. One patient, who presented with fatal brain metastasis, was excluded from further analysis. Of the remaining 68 patients, 30 were men and 38 were women. The average age at diagnosis was 52 years, and mean follow-up was 13.2 years. Mean survival was 7.7 years. Overall survival (OS) rates at 5, 10, and 15 years were 72%, 44%, and 34%, and cause-specific survival was 83%, 71%, and 55%, respectively. Recurrence-free survival rates were 65%, 52%, and 30% at 5, 10, and 15 years, with a total of 29 of 68 (43%) eventually suffering a recurrence. Overall survival was adversely affected by advancing T and AJCC stage. Higher tumor grades were also associated with decreased OS, although the numbers compared were small. Primaries of the nasosinal region fared poorly when compared with other locations. Total recurrence-free survival, local and distant recurrence rates were distinctly better in primaries of the oral cavity/oropharynx when compared with those in other locations. Reduced distant recurrence-free survival was significantly associated with increasing stage. No other variables were predictive for recurrence. Additionally, we found that nasosinal tumors were more likely to display higher stage at presentation, and were more often associated with perineural invasion. Also of interest was the association of perineural invasion with margin status, with 15 of 20 patients with positive margins displaying perineural invasion, while only 5 of 17 with negative margins showed nerve invasion (P = 0.02). On immunohistochemistry, 2 cases of the 29 (7%) tumor specimens found displayed HER-2/neu positivity. No correlation between clinical behavior and positive staining could be demonstrated. Our data concur with previous reports on ACC in terms of survival and recurrence statistics. Stage and site of primary were important determinants of outcome. Grade may still serve a role in decision making. We could not demonstrate any differences attributable to primary modality of therapy, perhaps due to the nonrandomization of patients into the various treatment tracks and the inclusion of palliative cases. Similarly, perineural invasion, radiation dose and field size, and HER-2/neu positivity did not prove to be important factors in our experience.

Molecular markers in head and neck squamous cell carcinoma: their biological function and prognostic significance.

Head and neck squamous cell carcinoma affects more than 500,000 people worldwide each year. Despite optimal treatment with surgery, irradiation, and chemotherapy, disease recurrence and progression remains a common and challenging oncological problem. Recently, interest has developed in identifying novel molecular markers that allow identification of those patients at increased risk for locoregional recurrence and death. This article reviews several such molecular markers studied in head and neck cancer, including p53, angiogenesis-related markers, cyclin D1, and epidermal growth factor receptor. The biological function of these markers and the potential clinical implications are discussed. The purpose of this review is to update the otolaryngologist on a rapidly emerging segment of applied translational research in our field.

BAG-1: a novel biomarker predicting long-term survival in early-stage breast cancer.

PURPOSE: Among women with early-stage breast cancer treated with lumpectomy and radiation therapy, 30% to 40% will develop metastatic disease, which is often fatal. A need exists therefore for biomarkers that distinguish patients at high risk of relapse. We performed a retrospective correlative analysis of BAG-1 protein expression in breast tumors derived from a cohort of early-stage breast cancer patients. PATIENTS AND METHODS: Archival paraffin blocks from 122 women with stages I to II breast cancer treated with lumpectomy and radiation therapy (median follow-up, 12.1 years) were analyzed by immunohistochemical methods using monoclonal antibodies recognizing BAG-1 and other biomarkers, including Bcl-2, estrogen receptor, progesterone receptor, p53, and HER2/Neu. Immunostaining data were correlated with distant metastasis-free survival (DMFS) and overall survival (OS). RESULTS: Cytosolic immunostaining for BAG-1 was upregulated in 79 (65%) of 122 invasive breast cancers (P <.001) compared with normal breast. Elevated BAG-1 was significantly associated with longer DMFS and OS, overall (stages 1 and II) and in node-negative (stage I only) patients, on the basis of univariate and multivariate analyses (DMFS, P =.005; OS, P =.01, in multivariate analysis of all patients; DMFS, P =.005; OS, P =.001, in multivariate analysis of node-negative patients). All other biomarkers failed to reach statistical significance in multivariate analysis. Clinical stage was an independent predictor of OS (P =.04) and DMFS (P =.02). CONCLUSION: These findings provide preliminary evidence that BAG-1 represents a potential marker of improved survival in early-stage breast cancer patients, independent of the status of axillary lymph nodes.

The location of contralateral breast cancers after radiation therapy.

Radiation therapy following conservative surgery results in scattered radiation to the contralateral breast, with higher doses to the medial breast and lower doses laterally. The purpose of the current study is to determine whether the location of contralateral breast cancers developing following breast conserving surgery and radiation is indicative of radiation-induced malignancies. The charts of 1,755 patients treated with conservative surgery and radiation therapy between 1970 and 1998 were reviewed. Fifty-nine patients who developed a contralateral malignancy following conservative surgery and radiation therapy and who had complete information and documentation of the location of the second lesion served as the primary focus of the current study. The location of the contralateral malignancy was compared with the location of the primary tumors of the overall patient population. The location of breast cancers developing in the contralateral breast following breast conserving therapy and radiation was not consistent with radiation-induced malignancies. Specifically, there was not a preponderance of medially located tumors in patients developing contralateral breast cancers following radiation. There was a slight excess of central lesions that cannot be explained by higher doses of radiation. The location of breast cancers in the contralateral breast following conservative surgery and radiation is not indicative of radiation-induced lesions. These data should be reassuring to women considering breast conserving surgery and radiation.

Breast-conserving therapy in the setting of collagen vascular disease.

BACKGROUND: It is unclear whether the presence of collagen vascular disease should be considered a contraindication to irradiation. This study was undertaken to determine whether women with pre-existing collagen vascular disease have an increased incidence of complications after breast-conserving therapy. METHODS AND MATERIALS: A cohort of 36 patients with documented collagen vascular disease was conservatively treated for early-stage breast cancer between 1975 and 1998. All of these patients were treated with conventional radiation therapy to a total medium dose of 64 Gy. Seventeen had rheumatoid arthritis; four, scleroderma; four, Raynaud's phenomenon; five, lupus erythematosus; two, Sjögren's disease; and four, polymyositis. Each of these patients was matched to two control patients without a history of collagen vascular disease on the basis of age, radiation therapytechnique, chemotherapy or hormone therapy use, tumor histology, and date of treatment. Acute and late complications were assessed using a six-point scale from the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer. The scoring system for both acute and late reactions ranged from 0 (no change over baseline) to 5 (radiation led to death). For the purpose of statistical analysis, patients were classified as having a significant complication if they had a score of 3 or greater. RESULTS: With a median clinical follow-up time of 12.5 years (range, 3.0-22.5 years), no significant difference was detected between the collagen vascular disease and control groups with respect to acute complications (14% vs 8%). With respect to late complications, a significant difference was observed (17% vs 3%) between the two groups. However, when patients in the collagen vascular disease group were analyzed by specific disease, this significance disappeared in all but the scleroderma group. CONCLUSIONS: Patients with scleroderma have a statistically significant increased incidence of radiation therapy complications after breast-conserving surgery and radiation therapy. The presence of other collagen vascular diseases should not be considered a contraindication for this treatment modality.

True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management.

PURPOSE: The purpose of this study was to classify all ipsilateral breast tumor relapses (IBTR) in patients treated with conservative surgery and radiation therapy (CS+RT) as either new primary tumors (NP) or true local recurrences (TR) and to assess the prognostic and therapeutic implications of this classification. METHODS AND MATERIALS: Of the 1152 patients who have been treated at Yale-New Haven Hospital before 1990, 136 patients have experienced IBTR as their primary site of failure. These relapses were classified as either NP or TR. Specifically, patients were classified as NP if the recurrence was distinctly different from the primary tumor with respect to the histologic subtype, the recurrence location was in a different location, or if the flow cytometry changed from aneuploid to diploid. This information was determined by a detailed review of each patient's hospital and/or radiotherapy record, mammograms, and pathologic reports. RESULTS: As of 2/99, with a mean follow-up of 14. 2 years, the overall ipsilateral breast relapse-free rate for all 1152 patients was 86% at 10 years. Using the classification scheme outlined above, 60 patient relapses were classified as TR, 70 were classified as NP and 6 were unable to be classified. NP patients had a longer mean time to breast relapse than TR patients (7.3 years vs. 3.7 years, p < 0.0001) and were significantly younger than TR patients (48.9 years vs. 54.5 years, p < 0.01). Patients developed both TR and NP at similar rates until approximately 8 years, when TR rates stabilized but NP rates continued to rise. By 15 years following original diagnosis, the TR rate was 6.8% compared to 13.1% for NP. Of the patients who had been previously tested for BRCA1/2 mutations, 17% (8/52) had deleterious mutations. It is noteworthy that all patients with deleterious mutations had new primary IBTR, while patients without deleterious mutations had both TR and NP (p = 0.06). Ploidy was evenly distributed between TR and NP but NP had a significantly lower S phase fraction (NP 13.1 vs. TR 22.0, p < 0.05). The overall survival following breast relapse was 64% at 10 years and 49% at 15 years. With a mean follow-up of 10.4 years following breast relapse, patients with NP had better 10-year overall survival (TR 55% vs. NP 75%, p < 0.0001), distant disease-free survival (TR 41% vs. NP 85%, p < 0.0001), and cause-specific survival (TR 55% vs. NP 90%, p < 0.0001). CONCLUSION: It appears that a significant portion of patients who experience ipsilateral breast tumor relapse following conservative surgery and radiation therapy have new primary tumors as opposed to true local recurrences. True recurrence and new primary tumor ipsilateral breast tumor relapses have different natural histories, different prognoses, and, in turn, different implications for therapeutic management.