Sandra S. Hatch

Lymph node involvement in immunohistochemistry-based molecular classifications of breast cancer

BACKGROUND Prognosis and treatment options differ for each molecular subtype of breast cancer, but risk of regional lymph node (LN) metastasis for each subtype has not been well studied. Since LN status is the most important predictor for prognosis, the aim of this study is to investigate the propensity for LN metastasis in each of the five breast cancer molecular subtypes. METHODS Under an institutional review board-approved protocol, we retrospectively reviewed the charts of all pathologically confirmed breast cancer cases from January 2004 to June 2012. Five subtypes were defined as luminal A (hormone receptor positive, Ki-67 low), luminal B (hormone receptor positive, Ki-67 high), luminal human epidermal growth factor receptor 2 (HER2), HER2-enriched (hormone receptor negative), and triple negative (TN). RESULTS A total of 375 patients with complete data were classified by subtype: 95 (25.3%) luminal A, 120 (32%) luminal B, 69 (18.4%) luminal HER2, 26 (6.9%) HER2-enriched, and 65 (17.3%) TN. On univariate analysis, age (<50), higher tumor grade, HER2+ status, tumor size, and molecular subtype were significant for LN positivity. Molecular subtype correlated strongly with tumor size (χ(2); P = 0.0004); therefore, multivariable logistic regression did not identify molecular subtype as an independent variable to predict LN positivity. CONCLUSIONS Luminal A tumors have the lowest risk of LN metastasis, whereas luminal HER2 subtype has the highest risk of LN metastasis. Immunohistochemical-based molecular classification can be readily performed and knowledge of the factors that affect LN status may help with treatment decisions.

Primary small cell neuroendocrine carcinoma of the vagina: a clinicopathologic study.

CONTEXT Primary small cell neuroendocrine carcinoma of the vagina is extremely rare, and its clinical behavior is aggressive. To our knowledge, 22 patients with this tumor have been reported in the English literature to date. OBJECTIVE To investigate 3 patients with this tumor clinically and pathologically. DESIGN The pathology database at the University of Texas Medical Branch at Galveston was searched, and 3 cases of primary small cell neuroendocrine carcinoma of the vagina were found. The histologic, immunohistochemical, and ultrastructural profiles of the tumors were investigated. The medical charts of the patients were reviewed, and the patients were followed up. PATIENTS Women with the diagnosis of primary small cell neuroendocrine carcinoma of vagina. RESULTS All 3 patients presented with advanced disease, and 2 patients died within 4 months of the initial diagnosis. One 38-year-old patient was newly diagnosed, and her clinical outcome had not yet been determined. The histologic features of all 3 tumors were similar to those of their pulmonary counterpart. All cases were positive for cytokeratin, chromogranin A, and synaptophysin. The expression pattern of thyroid transcription factor 1 was examined in all 3 patients, of whom 2 were negative and 1 was positive with negative clinical and radiologic thyroid or pulmonary findings. Ultrastructural evaluation showed scattered intracytoplasmic electron-dense neurosecretory granules. CONCLUSION Primary small cell neuroendocrine carcinoma of the vagina has histologic, immunohistochemical, and ultrastructural features similar to those of its pulmonary counterpart. Because thyroid transcription factor 1 can be positive, it should not be used to differentiate primary from metastatic disease. The current therapies have usually resulted in poor outcomes, and new therapeutic modalities should be explored.

Addition of chemotherapy to definitive radiotherapy for IB1 and IIA1 cervical cancer: Analysis of the National Cancer Data Base

PURPOSE The standard treatment for stage IB1 and IIA1 cervical carcinoma is surgery. For non-operative cases, the National Comprehensive Cancer Network recommends definitive radiotherapy (RT) with or without chemotherapy. This study sought to determine whether the addition of chemotherapy to RT improved overall survival (OS) for patients with stage IB1 and IIA1 cervical cancer. METHODS We used the National Cancer Data Base to identify patients with stage IB1 or stage IIA1 cervical cancer diagnosed in 2004 to 2012 who received definitive RT with or without chemotherapy. Patient, tumor, and treatment facility characteristics were assessed. Kaplan-Meier analysis was performed to compare overall survival (OS) between groups. Cox regression analysis was performed to identify factors associated with survival. Propensity-score matching was used to compare survival outcomes while accounting for indication bias. RESULTS 825 patients met the specified criteria. 275 (33.3%) of patients received treatment with RT alone, whereas 550 (66.7%) were treated with CRT. The median OS in patients treated with RT alone was 121.1months, while the median OS for patients treated with CRT was not reached (hazard ratio [HR]=0.719; 95% confidence interval [CI] 0.549-0.945). Propensity-score matched analysis confirmed that CRT was superior to RT alone (HR=0.701; 95% CI 0.509 to 0.963). CONCLUSIONS Our study suggests the addition of chemotherapy to definitive RT in patients with stage IB1 or stage IIA1 cervical cancer is associated with an improvement in OS. Prospective studies are recommended to validate these results and to further investigate the quality of life differences associated with chemotherapy use.

2-Methoxyestradiol, an Endogenous Estrogen Metabolite, Sensitizes Radioresistant MCF-7/FIR Breast Cancer Cells Through Multiple Mechanisms

PURPOSE The requirement for a well-tolerated and highly effective radiosensitizer that preferentially sensitizes tumor cells at multiple levels of radioresistance remains largely unmet. 2-Methoxyestradiol (2ME) has polypharmacological profiles that target multiple signaling pathways involved in the development of radioresistance. In the current study, we investigated the radiosensitizing effect of 2ME on the radioresistant breast cancer MCF-7/FIR cell line and explored the underlying mechanisms. METHODS AND MATERIALS The radiosensitizing effect of 2ME was evaluated on the basis of cell death and clonogenic survival. Formation of reactive oxygen species (ROS), apoptosis, and cell cycle progression were assessed by flow cytometry. Radiation-induced DNA damage was evaluated on the basis of histone γ-H2AX phosphorylation and foci formation. Immunoblotting was used to assess the effects of γ radiation and/or 2ME on radioresistance pathways. RESULTS Our data demonstrate that MCF-7/FIR cells expressed higher levels of Bcl-2 and HIF-1α and displayed a lower ROS phenotype than the parental MCF-7 cells. Treatment of parental MCF-7 cells with 2ME (0.5 μM) had minimal effect on γ radiation-induced cell proliferation and surviving fractions. On the contrary, in MCF-7/FIR cells, treatment with 2ME significantly enhanced γ radiation-induced reduction in cell proliferation and surviving fraction. This combination was effective in activating apoptosis, arresting the cell cycle at the G(2)/M phase, and increasing the level of γ radiation-induced ROS and the number of γ-H2AX foci. In addition, 2ME significantly ameliorated γ radiation-induced expression of the HIF-1α transcription factor and its downstream targets AKT/mTOR. CONCLUSION 2ME preferentially sensitizes radioresistant MCF-7/FIR cells to γ radiation by targeting multiple signaling pathways involved in the development of radioresistance. This polypharmacological profile qualifies 2ME as a promising radiosensitizer in the treatment of radioresistant breast cancer cells and warrants systematic preclinical and clinical studies.

The relationship between depressive symptoms and shoulder mobility among older women: assessment at one year after breast cancer diagnosis

Objective: To examine the association between depressive symptoms and shoulder range of motion at one year after breast cancer diagnosis, controlling for patient characteristics, tumour stage and cancer therapy (surgery, axillary node dissection and radiation). Design: Prospective trial of nurse case management involving 187 older women with complete data, age 60 years and older, newly diagnosed with breast cancer, from 1 November, 1993 to 31 October, 1996 in south-eastern Texas. Depressive symptoms, sociodemographic characteristics and breast cancer treatment were measured at two months and shoulder range of motion at 12 months. The relationship among the variables was evaluated with bivariate chi-square statistics and logistic regression analysis. All logistic models also included a variable indicating whether or not the woman received nurse case management, to control for intervention status. Results: Increasing depressive symptoms at baseline were associated with lower arm mobility at 12 months following breast cancer diagnosis. Each unit increase in depressive symptoms at baseline was associated with an 8% decreased odds of having full range of motion of the shoulder (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.87, 0.97), after controlling for relevant patient and treatment factors. Conclusion(s): Older women with depressive symptoms have an elevated risk of not fully recovering shoulder mobility after being treated for breast cancer. Future studies are needed to assess benefits from early intervention with psychological and or physical interventions in the presence of depressive symptoms on shoulder mobility.

Accelerated partial breast irradiation: Past, present, and future

Accelerated partial breast irradiation (APBI) focuses higher doses of radiation during a shorter interval to the lumpectomy cavity, in the setting of breast conserving therapy for early stage breast cancer. The utilization of APBI has increased in the past decade because of the shorter treatment schedule and a growing body of outcome data showing positive cosmetic outcomes and high local control rates in selected patients undergoing breast conserving therapy. Technological advances in various APBI modalities, including intracavitary and interstitial brachytherapy, intraoperative radiation therapy, and external beam radiation therapy, have made APBI more accessible in the community. Results of early APBI trials served as the basis for the current consensus guidelines, and multiple prospective randomized clinical trials are currently ongoing. The pending long term results of these trials will help us identify optimal candidates that can benefit from ABPI. Here we provide an overview of the clinical and cosmetic outcomes of various APBI techniques and review the current guidelines for selecting suitable breast cancer patients. We also discuss the impact of APBI on the economics of cancer care and patient reported quality of life.

Outcomes associated with adjuvant radiation after lumpectomy for elderly women with T1-2N0M0 triple-negative breast cancer: SEER analysis.

39 Background: Adjuvant Radiation (RT) may be omitted for elderly women with early stage breast cancer having favorable estrogen receptor status, however in the setting of triple negative breast cancer (TNBC), less evidence exists to guide decision making. As some findings thus far have shown TNBC to have an increased recurrence rate, this is an important subject to address. The purpose of this study is to use the Surveillance, Epidemiology, and End Result (SEER) database to evaluate how the addition of adjuvant radiation affects the survival of women ages 70 and above with T1-2, N0, M0 TNBC that undergo Lumpectomy (L). METHODS Cases diagnosed from 2010-2011 were downloaded from the SEER Database. Inclusion criteria were ages 70 and above, with T1-2N0M0 TNBC. Kaplan meier curves calculated overall survival (OS) and disease specific survival (DSS) in months (m). Log-Rank tests were performed to compare survival. Cox multivariate regression was performed to calculate Hazard Ratios (HR) and control for confounding variables including neoadjuvant chemotherapy, number of lymph nodes sampled, age, laterality, grade, T stage, extent of surgery, existence of other cancers. RESULTS From 2010-2011, SEER contained 109,559 cases of breast cancer with recorded results of Her-2-neu (H2N) status. Combining other receptor values, showed 12,620 triple-negative, which was 12% of cases. Of these, 6980 (55%) had stage T1-2, N0, M0. Lumpectomy was used in 4002 of these cases. There were 974 lumpectomy cases of women aged 70 and above. RT was given in 662 (68%) cases. After 23 months, L+ RT was associated with improved OS at 98.2% compared to 85.6% for L only (p=<0.001), as well as DSS at 99% for L+RT better than 94% for L only (p=0.003). Cox Regression showed radiation demonstrated improved OS (HR=0.14, p<0.001) and DSS (0.14, p=0.01). CONCLUSIONS The use of adjuvant RT after lumpectomy for elderly women with early stage TNBC was associated with improved OS and DSS. Noting the potential for selection bias in this study, future prospective study is required to define the management of early stage triple negative breast cancer.

Radiation Oncology Resident In-Training Examination

Radiation Oncology Resident In-Training Examination Sandra S. Hatch, MD, FACR,* Neha Vapiwala, MD,y Seth A. Rosenthal, MD, FACR,z John P. Plastaras, MD, PhD,y Albert L. Blumberg, MD, FACR,x William Small Jr, MD, FACR,jj Matthew J. Wenger, BBA,{ and Marie E. Taylor, MD, FACR, *University of Texas Medical Branch, Galveston, Texas; yUniversity of Pennsylvania, Philadelphia, Pennsylvania; zDepartment of Radiation Oncology, Sutter Cancer Center, Sacramento, California; xGreater Baltimore Medical Center, Baltimore, Maryland; jjStritch School of Medicine, Loyola University, Chicago, Illinois; {ITPG, Inc., Vienna, Virginia; and Baptist Memorial Hospital East, Memphis, Tennessee

Severe radiation therapy-related soft tissue toxicity in a patient with porphyria cutanea tarda: A literature review

Some porphyrias are associated with cutaneous phototoxicity due to photoactivation of porphyrins, but whether ionizing radiation can have an additive effect is not clear. We report a case of severe radiation therapy‐related toxicity in a patient with porphyria cutanea tarda and review the literature.

Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy

PurposeThis is the largest study to date evaluating response rates and pathologic complete response (pCR) and predictors thereof, based on molecular subtype, in women with breast cancer having undergone neoadjuvant chemotherapy (NC).MethodsThe National Cancer Database was queried for women with cT1-4N1-3M0 breast cancer having received NC. Patients were divided into four subtypes: luminal A, luminal B, Her2, or triple negative (TN). Multivariable logistic regression ascertained factors associated with developing pCR. Kaplan–Meier analysis evaluated overall survival (OS) between patients by degree of response to NC when stratifying patients by subtype.ResultsOf a total of 13,939 women, 322 (2%) were luminal A, 5941 (43%) luminal B, 2274 (16%) Her2, and 5402 (39%) TN. Overall, 19% of all patients achieved pCR, the lowest in luminal A (0.3%) and the highest in Her2 (38.7%). Molecular subtype was an independent predictor of both pCR and OS in this population. Clinical downstaging was associated with improved survival, mostly in women with luminal B, Her2, and TN subtypes. Subgroup analysis of the pCR population demonstrated 5-year OS in the luminal B, Her2, and TN cohorts of 93.0, 94.2, and 90.6%, respectively (Her2 vs. TN, p = 0.016).ConclusionsAssessing nearly 14,000 women from a contemporary United States database, this is the largest known study examining the relationship between response to NC and molecular subtype. Women with luminal A disease are the least likely to undergo pCR, with the highest rates in Her2 disease. Degree of response is associated with OS, especially in luminal B, Her2, and TN patients. Despite the comparatively higher likelihood of achieving pCR in TN cases, this subgroup may still experience a survival detriment, which has implications for an ongoing national randomized trial.