Sushil Beriwal

Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation.

Androgens exert growth inhibitory effects on estrogen receptor and progesterone receptor-negative breast cancer cell lines that show androgen receptor expression. These laboratory findings may be translated into inexpensive alternative therapies for hormone receptor-negative invasive breast cancers. Our aim was to systematically evaluate androgen receptor expression by immunohistochemistry in invasive breast cancers. Androgen receptor (clone AR441, Dako) expression was analyzed on 189 well-characterized consecutive invasive breast carcinomas represented with threefold redundancy on tissue microarrays. Androgen receptor expression was semi-quantitated using a histochemical score-like method and a score >10 was considered positive. Of the 189 consecutive invasive breast cancers, 151 (80%) were positive and 38 (20%) were negative for androgen receptor. The majority (95%) of estrogen receptor-positive tumors were also androgen receptor positive. Of the estrogen receptor-negative tumors, androgen receptor reactivity was seen in 3 of 30 (10%) triple-negative cases and in 5/8 (63%) estrogen receptor-negative/progesterone receptor-negative/HER2+ cases. Six of eight estrogen receptor-negative/androgen receptor-positive cases showed apocrine differentiation. Androgen receptor expression in estrogen receptor-positive cases was associated with smaller tumor size (P=0.0001), lower Nottingham grade (P=0.002) and less frequent tumor cell necrosis (P=0.0001). Androgen receptor expression in estrogen receptor-negative tumors was associated with lower Nottingham grade (P=0.005) and apocrine differentiation (P=0.039). In conclusion, most estrogen receptor-positive breast tumors also express androgen receptor. Androgen receptor expression in estrogen receptor-negative/progesterone receptor-negative/HER2+ tumors (which commonly show apocrine differentiation) and a subset of triple - negative apocrine tumors suggest that these tumors together comprises the ‘molecular apocrine’ group described previously. However, these findings should be further confirmed on larger series of triple-negative and estrogen negative/progesterone negative/HER2+ tumors. Androgen receptor-targeted therapy in estrogen/progesterone receptor-negative tumors may provide an inexpensive alternative to usual high-dose chemotherapy with or without trastuzumab.

Consensus Guidelines for Delineation of Clinical Target Volume for Intensity-Modulated Pelvic Radiotherapy for the Definitive Treatment of Cervix Cancer

PURPOSE Accurate target definition is vitally important for definitive treatment of cervix cancer with intensity-modulated radiotherapy (IMRT), yet a definition of clinical target volume (CTV) remains variable within the literature. The aim of this study was to develop a consensus CTV definition in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group. METHODS AND MATERIALS A guidelines consensus working group meeting was convened in June 2008 for the purposes of developing target definition guidelines for IMRT for the intact cervix. A draft document of recommendations for CTV definition was created and used to aid in contouring a clinical case. The clinical case was then analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants. RESULTS Nineteen experts in gynecological radiation oncology generated contours on axial magnetic resonance images of the pelvis. Substantial STAPLE agreement sensitivity and specificity values were seen for gross tumor volume (GTV) delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < 0.0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate. CONCLUSIONS This report provides guidelines for CTV definition in the definitive cervix cancer setting for the purposes of IMRT, building on previously published guidelines for IMRT in the postoperative setting.

American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy.

PURPOSE This report presents an update to the American Brachytherapy Society (ABS) high-dose-rate (HDR) brachytherapy guidelines for locally advanced cervical cancer. METHODS Members of the ABS with expertise in cervical cancer formulated updated guidelines for HDR brachytherapy using tandem and ring, ovoids, cylinder, or interstitial applicators for locally advanced cervical cancer. These guidelines were written based on medical evidence in the literature and input of clinical experts in gynecologic brachytherapy. RESULTS The ABS affirms the essential curative role of tandem-based brachytherapy in the management of locally advanced cervical cancer. Proper applicator selection, insertion, and imaging are fundamental aspects of the procedure. Three-dimensional imaging with magnetic resonance or computed tomography or radiographic imaging may be used for treatment planning. Dosimetry must be performed after each insertion before treatment delivery. Applicator placement, dose specification, and dose fractionation must be documented, quality assurance measures must be performed, and followup information must be obtained. A variety of dose/fractionation schedules and methods for integrating brachytherapy with external-beam radiation exist. The recommended tumor dose in 2-Gray (Gy) per fraction radiobiologic equivalence (normalized therapy dose) is 80-90Gy, depending on tumor size at the time of brachytherapy. Dose limits for normal tissues are discussed. CONCLUSION These guidelines update those of 2000 and provide a comprehensive description of HDR cervical cancer brachytherapy in 2011.

Mammaglobin vs GCDFP-15 : An immunohistologic validation survey for sensitivity and specificity

There are limited data that compare the usefulness of mammaglobin with gross cystic disease fluid protein-15 (GCDFP-15) in the identification of breast carcinomas. Whole tissue sections of 29 breast carcinomas with matched lymph node metastases and 63 breast carcinomas on tissue microarray were stained with mammaglobin cocktail and GCDFP-15 antibodies. In addition, tissue microarrays (US Biomax, Rockville, MD) containing 544 different human tumors were also stained with the mammaglobin antibody cocktail. Positive staining was seen in 67 (55.4%) of 121 breast carcinomas with mammaglobin and in 28 cases (23.1%) with GCDFP-15. In the majority of cases, the staining intensity and number of cells staining were higher with mammaglobin than with GCDFP-15. Positive mammaglobin staining was also seen in 44 (8.1%) of 544 nonbreast tumors. Mammaglobin is a more sensitive marker than GCDFP-15 for breast carcinoma; however, it lacks the specificity of GCDFP-15.

Histopathologic variables predict Oncotype DX recurrence score.

Oncotype DX™ is a commercially available reverse transcriptase-polymerase chain reaction based assay that provides a Recurrence Score (RS) and has been shown to provide prognostic and predictive information in estrogen receptor-positive lymph node-negative breast cancers. Independent studies of its utility in routine practice are lacking. Slides and surgical pathology reports from 42 cases of breast carcinomas evaluated by Oncotype DX™ were retrospectively reviewed to determine patient age, tumor size, histologic grade, estrogen and progesterone receptor (ER and PR) and ERBB2 (HER-2/neu) data, with ER and PR reported as a semi-quantitative score reflecting both intensity of staining and proportion of positive cells. We show here that Recurrence Score is significantly correlated with tubule formation, nuclear grade, mitotic count, ER immunohistochemical score, PR immunohistochemical score, and HER-2/neu status, and that the equation RS=13.424+5.420 (nuclear grade) +5.538 (mitotic count) −0.045 (ER immunohistochemical score) −0.030 (PR immunohistochemical score) +9.486 (HER-2/neu) predicts the Recurrence Score with an R2 of 0.66, indicating that the full model accounts for 66% of the data variability. Although the Oncotype DX™ Recurrence Score holds potential, further validation of its independent value beyond that of histopathologic analysis is necessary before it can be implemented in clinical decision making.

American Brachytherapy Society consensus guidelines for adjuvant vaginal cuff brachytherapy after hysterectomy

PURPOSE To develop recommendations for the use of adjuvant vaginal cuff brachytherapy after hysterectomy and update previous American Brachytherapy Society (ABS) guidelines. METHODS AND MATERIALS A panel of members of the ABS performed a literature review, supplemented their clinical experience, and formulated recommendations for adjuvant vaginal cuff brachytherapy. RESULTS The ABS endorses the National Comprehensive Cancer Network guidelines for indications for radiation therapy for patients with endometrial cancer and cervical cancer and the guidelines on quality assurance of the American Association on Physicists in Medicine. The ABS made specific recommendations for applicator selection, insertion techniques, target volume definition, dose fractionation, and specifications for postoperative adjuvant vaginal cuff therapy. The ABS recommends that applicator selection should be based on patient anatomy, target volume geometry, and physician judgment. The dose prescription point should be clearly specified. Suggested doses were tabulated for treatment with brachytherapy alone, and in combination with external beam radiation therapy, when applicable. A properly fitted brachytherapy applicator should be selected that conforms to the vaginal apex and achieves mucosal contact with optimal tumor and normal tissue dosimetry. Dose prescription points may be individually selected but doses should be reported at the vaginal surface and at 0.5-cm depth. CONCLUSIONS Recommendations are made for adjuvant vaginal cuff brachytherapy. Practitioners and cooperative groups are encouraged to use these recommendations to formulate their treatment and dose reporting policies. These recommendations will permit meaningful comparisons of reports from different institutions and lead to better and more appropriate use of vaginal brachytherapy.

Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy: a single institutional experience with 359 cases.

Complete pathologic response to neoadjuvant chemotherapy (NACT) is predominantly seen in “ERBB2” and “basal‐like” tumors using expression profiling. We hypothesize that a similar response could be predicted using semiquantitative immunohistochemistry for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2).

American Brachytherapy Society consensus guidelines for interstitial brachytherapy for vaginal cancer

PURPOSE To present recommendations for the use of interstitial brachytherapy in patients with vaginal cancer or recurrent endometrial cancer in the vagina. METHODS A panel of members of the American Brachytherapy Society reviewed the literature, supplemented that with their clinical experience, and formulated recommendations for interstitial brachytherapy for primary or recurrent cancers in the vagina. RESULTS Patients with bulky disease (approximately >0.5cm thick) should be considered for treatment with interstitial brachytherapy. The American Brachytherapy Society reports specific recommendations for techniques, target volume definition, and dose-fractionation schemes. Three-dimensional treatment planning is recommended with CT scan and/or MRI. The treatment plan should be optimized to conform to the clinical target volume and should reduce the dose to critical organs, including the rectum, bladder, urethra, and sigmoid colon. Suggested doses in combination with external beam radiation therapy and summated equivalent doses in 2Gy fractions are tabulated. CONCLUSION Recommendations are made for interstitial brachytherapy for vaginal cancer and recurrent disease in the vagina. Practitioners and cooperative groups are encouraged to use these recommendations to formulate treatment and dose-reporting policies. Such a process will result in meaningful outcome comparisons, promote technical advances, and lead to appropriate utilization of these techniques.

PET-CT in radiation oncology: the impact on diagnosis, treatment planning, and assessment of treatment response.

Objective:To review the role of hybrid positron emission tomography (PET)-computed tomography (CT) systems in the design and management of cancer patients in the modern radiation oncology practice. PET is co-registered with CT and incorporated into a systematic approach to the staging, management, and assessment of response and surveillance of a variety of oncologic diagnoses. Methods:A review of the literature of functional imaging such as PET-CT in staging, treatment plan design, assessment of response and detection of recurrence for tumors involving the head and neck, lung, esophagus, rectum amongst others. Results:PET and PET-CT offer significant advantages which include more accurate staging which often results in management changes in roughly one-third of patients across a number of disease site. More accurate target definition may augment highly conformal radiation treatment plans using intensity-modulated radiation therapy and stereotactic radiosurgery and radiotherapy. Conclusion:The emerging data appears to suggest the functional imaging may be a more useful tool to evaluate the therapeutic effect of treatment, detect early failures and prognosticate long-term outcome.

Breast-Conserving Therapy after Neoadjuvant Chemotherapy: Long-term Results

Abstract:  The purpose of this study was to determine patterns of ipsilateral breast tumor recurrence (IBTR) and local‐regional recurrence (LRR) after neoadjuvant chemotherapy and breast‐conserving therapy (BCT). A total of 153 breast cancer patients were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy between 1980 and 2002. The clinical stage (American Joint Committee on Cancer [AJCC] 1997) at diagnosis was IIA in 22%, IIB in 28%, IIIA in 39%, and IIIB in 11%. The prechemotherapy T size distribution was less than 2 cm in 5 patients, 2.1–5 cm in 100 patients, and greater than 5.1 cm in 48 patients. Sixty‐seven patients (44%) underwent cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF)‐based chemotherapy and 86 (56%) underwent Adriamycin‐based chemotherapy. Thirty‐seven patients (24%) had a complete pathologic response in the breast. All procedures were performed by a single surgeon (G.F.S.). The surgery was local excision alone in 19 patients, local excision and axillary lymph node dissection (ALND) in 130 patients, and ALND alone in 4 patients. Eleven patients had positive surgical margins. Rates of LRR‐, IBTR‐, and distant metastasis (DM)‐free survival were calculated by the Kaplan–Meier method. Patient and pathologic variables were then analyzed in an attempt to identify predictors of clinical outcome. With a median follow‐up period of 55 months (range 6–200 months), eight patients developed LRR, five of which were classified as IBTR. Five‐ and 10‐year actuarial rates of LRR‐free, IBTR‐free, and DM‐free survival were 93% and 88%, 96% and 91%, and 70% and 58%, respectively. Pretreatment and pathologic parameters that positively correlated with IBTR were advanced stage (p = 0.03) and margin positivity (p = 0.04). No other clinical factors were predictive of higher recurrence. BCT results in a low rate of IBTR and LRR in appropriately selected patients. Advanced stage at presentation is associated with increased risk of IBTR, although overall recurrence is low. In selected cases, BCT is safe and an effective alternative to mastectomy.