Dharamvir Jain

Increasing use of elective mastectomy and contralateral prophylactic surgery among breast conservation candidates: a 14-year report from a comprehensive cancer center.

Background: First-line surgical options for early-stage breast cancer include breast-conserving surgery (BCS) or mastectomy. We analyzed factors that influence the receipt of mastectomy and resultant trends over time. Methods: We analyzed the rates of mastectomy and BCS for 1634 women who underwent upfront surgical treatment for AJCC stage 0, I, or II breast cancer between 1995 and 2008 using data from the University of Louisville James Graham Brown Cancer Center Tumor Registry. We examined the trend of treatment over time and assessed the probability of receiving mastectomy using multivariate logistic regression. Results: Overall, 65.9% of women received BCS, and 34.1% received mastectomy over a 14-year period (annual BCS rate range, 38.6% to 77.7%). The mastectomy rate substantially decreased from 43.5% in 1995 to 22.5% in 2004 (P=0.0007) but then increased to 51.7% in 2008 (P<0.0001). During the years between 2004 and 2008 (vs. 1995 to 2003), there was a significant increase in the rates of mastectomy performed in conjunction with immediate reconstruction (IR: 35.7% vs. 8.4%; P<0.0001) and/or contralateral prophylactic mastectomy (CPM: 22.9% vs. 3.3%; P<0.0001). On the basis of the multivariate analysis, the rate of receiving mastectomy was drastically higher for patients treated since 2004 (vs. before 2004), uninsured and government-insured (vs. privately insured) patients, patients with pT2 disease (vs. pTis or pT1), patients with pN1 disease (vs. pNX or pN0). Conclusions: In this longitudinal registry study, major independent determinants of mastectomy for early-stage breast cancer include year of diagnosis, insurance status, and stage. Mastectomy rates declined until 2004, but have since increased in conjunction with immediate reconstruction and contralateral prophylactic mastectomy. Additional study is needed to identify the underlying reasons for and unintended consequences of the reemergence of radical surgery for early-stage breast cancer in the era of multidisciplinary care.

Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype.

Tumor-associated macrophages (TAM) with an alternatively activated phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. In this study, we demonstrate that particulate yeast-derived β-glucan, a natural polysaccharide compound, converts polarized alternatively activated macrophages or immunosuppressive TAM into a classically activated phenotype with potent immunostimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, Krebs cycle, and glutamine utilization. In addition, particulate β-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1–induced spleen tyrosine kinase–Card9–Erk pathway. Further in vivo studies show that oral particulate β-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate β-glucan–treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared with those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate β-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed light on the action mode of β-glucan treatment in cancer.

A Phase 2 Trial of Once-Weekly Hypofractionated Breast Irradiation: First Report of Acute Toxicity, Feasibility, and Patient Satisfaction

PURPOSE To report on early results of a single-institution phase 2 trial of a 5-fraction, once-weekly radiation therapy regimen for patients undergoing breast-conserving surgery (BCS). METHODS AND MATERIALS Patients who underwent BCS for American Joint Committee on Cancer stage 0, I, or II breast cancer with negative surgical margins were eligible to receive whole breast radiation therapy to a dose of 30 Gy in 5 weekly fractions of 6 Gy with or without an additional boost. Elective nodal irradiation was not permitted. There were no restrictions on breast size or the use of cytotoxic chemotherapy for otherwise eligible patients. Patients were assessed at baseline, treatment completion, and at first posttreatment follow-up to assess acute toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and quality of life (European Organization for Research and Treatment of Cancer QLQ-BR23). RESULTS Between January and September 2011, 42 eligible patients underwent weekly hypofractionated breast irradiation immediately following BCS (69.0%) or at the conclusion of cytotoxic chemotherapy (31.0%). The rates of grade ≥2 radiation-induced dermatitis, pain, fatigue, and breast edema were 19.0%, 11.9%, 9.5%, and 2.4%, respectively. Only 1 grade 3 toxicity-pain requiring a course of narcotic analgesics-was observed. One patient developed a superficial cellulitis (grade 2), which resolved with the use of oral antibiotics. Patient-reported moderate-to-major breast symptoms (pain, swelling, and skin problems), all decreased from baseline through 1 month, whereas breast sensitivity remained stable over the study period. CONCLUSIONS The tolerance of weekly hypofractionated breast irradiation compares well with recent reports of daily hypofractionated whole-breast irradiation schedules. The regimen appears feasible and cost-effective. Additional follow-up with continued accrual is needed to assess late toxicity, cosmesis, and disease-specific outcomes.

Locoregional recurrence in patients with triple-negative breast cancer: preliminary results of a single institution study.

Purpose: To examine the impact of radiotherapy on breast cancer patients with triple-negative (ER-, PR-, HER2/neu-) disease. Materials and Methods: A prospectively collected database of 152 triple negative breast cancer patients was initiated in 2004. A total of 77 patients who had all phases of their therapy (surgery, chemotherapy, and radiotherapy) at our institution with a minimum of 2-months follow-up are included. Patients with all types of surgery (lumpectomy or mastectomy), chemotherapy (neoadjuvant or adjuvant), and radiotherapy (tangents only or comprehensive nodal irradiation) are included. Patients received radiotherapy in the setting of breast-conservation and in the postmastectomy setting for ≥5 cm primary tumors and/or ≥4 positive lymph nodes. Patients were divided into 2 groups for statistical analysis, based on whether they received radiotherapy or not. Results: In the cohort, 53 (69%) received radiotherapy, 24 (31%) received no radiotherapy. The median follow-up was 23.2 months (range, 2.0–63.1). In the alive patients, the median follow-up time was 25.6 (range, 2.0–63.1) months. Patients who received radiotherapy were significantly more likely to be of a higher AJCC stage (P < 0.001) than patients who did not receive radiotherapy. Of the patients who received radiotherapy, 33 (61.1%) did so for breast conservation. For the entire group, 1- and 3-year overall survivals are 90.9% and 86.3%, respectively. The 3-year actuarial locoregional relapse-free survival probability for patients who received radiation was higher than those who did not receive radiation (79.6% vs. 57.9%, P = 0.049). Conclusions: Despite significantly lower AJCC stage, patients with triple-negative breast cancer who do not undergo radiotherapy have a significantly higher risk of locoregional recurrence.

Delay of adjuvant chemotherapy after elective mastectomy and immediate reconstruction in breast-conservation candidates: a matched-pair analysis.

Objectives:To analyze factors that influence the timing of adjuvant chemotherapy in patients who are candidates for breast-conservation therapy (BCT) but elect mastectomy with immediate reconstruction (M-IR). Methods:We identified 35 consecutively treated patients with stage I or II breast cancer between 2004 and 2009 who underwent M-IR and adjuvant chemotherapy from the University of Louisville Cancer Registry. We matched these patients for age and AJCC stage to 35 controls who underwent BCT and adjuvant chemotherapy. We examined the timing and delay of initiation of chemotherapy using univariate logistic regression and McNemar test for matched pairs. Results:For the 70 patients evaluated, the median age was 46 years (range, 30 to 65 y), and the distribution for stage I, IIA, and IIB was 22.9%, 65.7%, and 11.4%, respectively. The 2 groups were well balanced in terms of race, rural/urban status, smoking, diabetes, insurance coverage, and histology. For BCT and M-IR, the median time to chemotherapy initiation was 38 days (range, 25 to 103 d) and 55 days (range, 30 to 165 d), respectively. Patients undergoing M-IR were more likely to experience any delay (>45 d; 54.3% vs. 22.9%; P<0.001) and/or significant delay (>90 d; 20.0% vs. 2.9%; P<0.001). On univariate logistic regression analysis, surgery type had a major impact on delay of chemotherapy (odds ratio=8.35; 95% confidence interval, 2.86-24.4; P<0.001). Conclusions:The use of M-IR in breast-conservation candidates independently predicts for delay in initiation of adjuvant chemotherapy. Further study is needed to qualify the causes and clinical significance of these delays.

Therapy-related leukaemia cutis: a review.

Leukaemia cutis following chemotherapy for a malignancy is a multifactorial process that is dependent on the chemotherapeutic agent used, the dosing regimen, and the cumulative dose as well as potential contributing therapies such as radiation and possibly even haematopoeitic support from granulocyte colony stimulating factor. In the right combination and in a patient with a conducive milieu of epigenetic factors, leukaemia can develop as a treatment complication. Leukaemia cutis is the specific infiltration of the skin by leukaemic cells and occurs most commonly when the underlying leukaemia is an acute myeloid leukaemia. Although it is well reviewed in the literature as a result of primary leukaemia, leukaemia cutis has only very rarely been reported in association with therapy‐induced leukaemia. This article reviews the factors that contribute to therapy‐related leukaemia and the development of leukaemia cutis.

Leukaemia cutis in a patient treated for breast cancer

A 47‐year‐old woman with a history of breast cancer presented with eruptive cutaneous nodules on the trunk and extremities. Treatment for her breast cancer had included surgery, radiation and chemotherapy with doxorubicin and cyclophosphamide. Biopsy of the skin lesions revealed leukaemia cutis, which led to the discovery of acute myelogenous leukaemia. This was felt to be primarily induced by doxorubicin. Treatment included induction chemotherapy in preparation for a bone marrow transplant, which resulted in the disappearance of the cutaneous lesions. However, the patient later succumbed to her leukaemia.

Age-related Disparity: Breast Cancer in the Elderly

Aging poses an unique opportunity to study cancer biology and treatment in older adults. Breast cancer is often studied in young women; however, much investigation remains to be done on breast cancer in our expanding elderly population. Diagnostic and management strategies applicable to younger patients cannot be empirically used to manage older breast cancer patients. Lack of evidence-based data continues to be the major impediment toward delivery of personalized cancer care to elderly breast cancer patients. This article reviews the relevant literature on management of curable breast cancer in the elderly, the role of geriatric assessment, complex treatment decision making within the context of patient’s expected life expectancy, comorbidities, physical function, socioeconomic status, barriers to health care delivery, goals of treatment, and therapy-related side effects. Continuing efforts for enrolling elderly breast cancer patients in contemporary clinical trials, and thus improving age-appropriate care, are emphasized.

High-dose versus weekly cisplatin definitive chemoradiotherapy for HPV-related oropharyngeal squamous cell carcinoma of the head and neck

OBJECTIVES To compare the outcomes and toxicity of high-dose cisplatin (HDC) versus weekly cisplatin (WC) definitive chemoradiotherapy (CRT) for patients with human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (SCCOPx). METHODS All patients with p16 positive SCCOPx treated with definitive CRT with cisplatin between 2010 and 2014 at a single institution were retrospectively reviewed. CTCAE v 4.03 toxicity criteria were used. The Kaplan-Meier method was used to estimate event-free survival (EFS) and the overall survival (OS). RESULTS Of the 55 patients included, 22 were patients treated with HDC at dose of 100mg/m2 on days 1 and 22; and the remaining 33 patients were treated with WC at 40mg/m2. Both cohorts received a median total dose of cisplatin of 200mg/m2. At median follow-up of 31months, there was one local failure and no distant failures in the HDC cohort. In the WC group, there were 6 total failures (2 local, 4 distant). Estimated 2-year EFS was better in HDC cohort as compared to WC (96% vs. 75%; p=0.04). There was no significant difference in 2-year OS (95% vs. 94%; p=0.40). Weight loss, gastric tube dependence at six months, acute renal injury and grade 3 or 4 hematological toxicity were all similar between both groups. CONCLUSIONS HPV-related SCCOPx treated with definitive CRT with either HDC or WC had similar toxicity profile. HDC had better EFS when compared with WC and this seems to be driven by increased distant failure rates, although the OS was similar.

A phase II trial of once-weekly hypofractionated breast irradiation (WHBI): Interim analysis of cosmetic outcome and quality of life.

67 Background: A planned interim analysis of an institutional Phase II trial of once-weekly radiotherapy for patients undergoing breast-conserving surgery (BCS). METHODS Patients who underwent BCS for AJCC Stage 0, I or II breast cancer with negative surgical margins were eligible to receive whole-breast radiotherapy to a dose of 30Gy in 5 weekly fractions of 6 Gy with or without an additional boost. There were no restrictions on age, breast size or the use of cytotoxic chemotherapy for otherwise eligible patients. Patients were evaluated at baseline, 6 and 12 months with digital photography, physician assessment of cosmesis (Harvard Scale) and self-assessment (BCTOS). RESULTS Between January 2011 and January 2013, 82 eligible patients underwent WHBI immediately following BCS (82.7%) or at the conclusion of adjuvant cytotoxic chemotherapy (17.3%). The median age was 60 years (range: 30-80y) and the median followup was 33.1 months and all patients had at least 1 year followup. The rate of Excellent/Good vs. Fair/Poor cosmesis at 12 months was 77.3% vs. 22.7%. The rate of significant cosmetic change from baseline was 14.7%. The only factor predictive of significant cosmetic change was smoking status (OR: 6.94; p = 0.016). The median BCTOS score increased only slightly from baseline (31) to one year (32), with patient-reported breast size differences worsening but complaints of pain improving over the study period. CONCLUSIONS Cosmetic outcome after WHBI compares well with reports of daily hypofractionated whole-breast irradiation. Further follow-up with continued accrual is needed to assess cosmetic stability and disease-specific outcomes. CLINICAL TRIAL INFORMATION NCT01278212.