Lior Z. Braunstein

CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation

Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.

Outcome Following Local‐Regional Recurrence in Women with Early‐Stage Breast Cancer: Impact of Biologic Subtype

Local‐regional recurrence (LRR) after breast‐conserving therapy (BCT) can result in distant metastasis and decreased disease‐free survival (DFS). This study examines factors associated with DFS following LRR. The initial population included 2,233 consecutive women who underwent BCT from 1998 to 2007. Biologic subtype was approximated using a combination of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. Cumulative incidence of DFS after LRR was calculated. The association of clinical, pathologic, and treatment parameters with DFS was evaluated using a Cox regression model. At a median follow‐up of 105 months, 82 patients (3.7%) had a LRR. Of these, 66 (80%) were in‐breast and 16 (20%) involved the ipsilateral lymph nodes. Twenty patients subsequently developed distant metastases. Five‐year DFS after initial recurrence was 69.6% for the overall cohort. On univariate analysis, triple‐negative disease (ER/PR/HER2 negative, TNBC) was associated with reduced DFS (HR = 3.8; 95% CI: 1.8–8.1; p < 0.001). Other factors associated with reduced DFS were larger tumor size (HR = 1.3; 95% CI: 1.03–1.6; p = 0.02), shorter interval from initial diagnosis to LRR (HR = 0.98 per month; 95% CI: 0.97–0.99; p = 0.02), and no salvage surgery (HR = 0.2; 95% CI: 0.09–0.5; p = 0.001). On multivariate analysis, TNBC remained the most significant factor associated with reduced DFS (HR = 4.8; 95% CI: 2.25–10.4; p < 0.001). Compared to women with luminal A disease, those with TNBC had significantly worse DFS (37.5% versus 88.3% at 5 years; p < 0.001). Women with TNBC who developed LRR were at high risk of subsequent recurrence. Efforts should be targeted toward both preventing initial recurrence and decreasing subsequent metastasis.

Immunosurveillance by Antiangiogenesis: Tumor Growth Arrest by T Cell–Derived Thrombospondin-1

Recent advances in cancer immunotherapy suggest that manipulation of the immune system to enhance the antitumor response may be a highly effective treatment modality. One understudied aspect of immunosurveillance is antiangiogenic surveillance, the regulation of tumor angiogenesis by the immune system, independent of tumor cell lysis. CD4(+) T cells can negatively regulate angiogenesis by secreting antiangiogenic factors such as thrombospondin-1 (TSP-1). In tumor-bearing mice, we show that a Th1-directed viral infection that triggers upregulation of TSP-1 in CD4(+) and CD8(+) T cells can inhibit tumor angiogenesis and suppress tumor growth. Using bone marrow chimeras and adoptive T-cell transfers, we demonstrated that TSP-1 expression in the T-cell compartment was necessary and sufficient to inhibit tumor growth by suppressing tumor angiogenesis after the viral infection. Our results establish that tumorigenesis can be stanched by antiangiogenic surveillance triggered by an acute viral infection, suggesting novel immunologic approaches to achieve antiangiogenic therapy.

Whole Pelvis Versus Prostate-Only Radiotherapy With or Without Short-Course Androgen Deprivation Therapy and Mortality Risk.

BACKGROUND The purpose of the study was to determine whether the extent of prostate radiotherapy (ie, whole-pelvic radiotherapy [WPRT] vs. prostate and seminal vesicle radiotherapy [PSVRT]) is associated with all-cause mortality (ACM) in men treated with or without androgen deprivation therapy (ADT). PATIENTS AND METHODS A multiple-institution cohort of 3709 prostate cancer patients was prospectively assembled from 1991 to 2006. The median age was 72 years and all patients had T1c-T3N0M0 adenocarcinoma of the prostate. Patients were treated with WPRT or PSVRT followed by a brachytherapy boost, with or without neoadjuvant ADT (median duration, 4.2 months). Seventy percent of patients had unfavorable-risk disease (Gleason score ≥ 7; prostate-specific antigen ≥ 10 ng/mL; or stage ≥ T2b). Cox regression was applied to determine whether the radiation treatment volume affected the risk of ACM. The interaction between radiation volume and ADT use was assessed. RESULTS After a median follow-up of 3.3 years, 561 deaths were observed. A decreased risk of ACM was noted with the use of WPRT versus PSVRT (adjusted hazard ratio [AHR], 0.58; 95% confidence interval [CI], 0.38-0.89; P = .01), or with ADT use (AHR, 0.71; 95% CI, 0.58-0.90; P = .004). However, a combination of WPRT and ADT did not further improve ACM compared with either WPRT alone or PSVRT with ADT. Moreover, there was a significant interaction between the radiotherapeutic treatment volume and ADT (AHR, 1.61; 95% CI, 1.004-2.58; P = .048). CONCLUSION Treatment with WPRT or short-course ADT is associated with a decreased risk of ACM, although a combination of the two does not yield greater benefit. This observation suggests a shared mechanism for this risk reduction, which we hypothesize to be via the treatment of micrometastatic disease within the pelvic lymph nodes.

Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer

Background. Increasing body mass index (BMI) is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT) for prostate cancer (PC) remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT). BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83%) received RT + ADT and, of these, 7 (70%) were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR): 0.18 [95% CI: 0.04–0.89]; P = 0.04), whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01–1.31]; P = 0.04). Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.

Potential Morbidity Reduction With Proton Radiation Therapy for Breast Cancer

Proton radiotherapy confers significant dosimetric advantages in the treatment of malignancies that arise adjacent to critical radiosensitive structures. To date, these advantages have been most prominent in the treatment of pediatric and central nervous system malignancies, although emerging data support the use of protons among other anatomical sites in which radiotherapy plays an important role. With advances in the overall treatment paradigm for breast cancer, most patients with localized disease now exhibit long-term disease control and, consequently, may manifest the late toxicities of aggressive treatment. As a result, there is increasing emphasis on the mitigation of iatrogenic morbidity, with particular attention to heart and lung exposure in those receiving adjuvant radiotherapy. Indeed, recent landmark analyses have demonstrated an increase in significant cardiac events that is linked directly to low-dose radiation to the heart. Coupled with practice-changing trials that have expanded the indications for comprehensive regional nodal irradiation, there exists significant interest in employing novel technologies to mitigate cardiac dose while improving target volume coverage. Proton radiotherapy enjoys distinct physical advantages over photon-based approaches and, in appropriately selected patients, markedly improves both target coverage and normal tissue sparing. Here, we review the dosimetric evidence that underlies the putative benefits of proton radiotherapy, and further synthesize early clinical evidence that supports the efficacy and feasibility of proton radiation in breast cancer. Landmark, prospective randomized trials are underway and will ultimately define the role for protons in the treatment of this disease.

Hypofractionated Whole Breast Irradiation for Early-Stage Breast Cancer

tant relative and 4571 (4.2%; 95% CI, 4.1%-4.3%) for whom the individual was not a blood or legal relative. This was most often a friend or an intimate relationship outside marriage (eg, “baby momma,” “common law spouse,” “live-in soul mate,” and “same-sex partner”). For 849 patients (<1%), the relationship involved another social tie, such as “landlady,” “priest,” “roommate,” or “sponsor.” Veterans younger than 65 years were more likely than those aged 65 years or older (9.2% vs 6.0%, respectively; P < .001) to have a next of kin who was not a nuclear family member.

ASO Author Reflections: Breast Cancer Local Recurrence Versus New Primary—Clinical Predictors and Prognostic Implications

It has long been observed that controlling a locally recurrent tumor that persisted despite definitive therapy is more challenging than the management of a de novo unselected primary cancer. Indeed, 10-year overall survival rates can approximate 40% following local recurrence, whereas overall breast cancer outcomes are significantly more favorable. An in-breast tumor recurrence (IBTR) may represent a true recurrence (TR) arising from the original tumor, or a new primary (NP). However, there is no standard approach for differentiating TRs from NPs. Some have used in-quadrant recurrence as an indicator of a TR, whereas others have used concordance of histology and subtype, all with variable reliability. Our study sought to establish the presence of an in situ component within an IBTR as a marker of a NP that, thereby, portends favorable disease-free survival (DFS). To date, the majority of breast cancer studies have focused on overall IBTR, likely overestimating treatment failures given the occasional presence of de novo carcinogenesis. PRESENT

Reply to "Questions About In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy"

Dr. Altundag raises an interesting question regarding the influence of breast cancer biologic subtype on survival after a local recurrence. Although we previously reported that subtype approximations do maintain prognostic significance after a first recurrence, in the context of the current study, this raises another issue about the propensity for a breast cancer recurrence to harbor ductal carcinoma in situ (DCIS) as a function of the primary disease subtype. This was addressed in Table 2, demonstrating no significant differences in the rates between true recurrence (TR) and new primaries (NP) by biologic subtype. In addition, with regard to the overall cohort from which these recurrences derive, the nearly 4000 patients treated with breast-conserving therapy (BCT) were representative of previously reported American population distributions of breast cancer biologic subtypes, including approximately 80% estrogen receptor-positive (ER?) lesions, the majority of which retained their luminal (ER?) subtype at the time of local recurrence. We currently are performing additional analyses to identify whether variations in subtype and location between primary and recurrent lesions are as informative as our DCIS definition of true recurrence versus new primary disease. Sincerely, James Laird, BA and Lior Z. Braunstein, MD

Abstract P4-12-04: Breast cancer subtype, age and lymph node status as predictors of local recurrence following breast-conserving therapy

Purpose/Objectives: Advances in breast-conserving therapy (BCT) have yielded local control rates comparable or superior to those of mastectomy. Here, we sought to identify risk factors associated with isolated local recurrence (LR) following BCT. Materials/Methods: This study included a multi-institutional cohort of 2,233 consecutive breast cancer patients who underwent BCT between 1998 and 2007. Patient characteristics and disease parameters were stratified by age, subtype and nodal status. Biologic subtype was approximated by receptor status and tumor grade. No patients received HER2/neu-directed therapy. The association of clinicopathologic features with LR was evaluated using Cox proportional hazards regression models. Results: At a median follow-up of 106 months, 69 LR events (3.1%) were observed. Among the overall cohort, 10-year freedom from LR was 95.9%. On univariate Cox regression analysis, risk factors associated with LR included subtype other than luminal A (hazard ratio [HR] for luminal B = 3.01, HER2 = 6.29, triple negative [TNBC] = 4.72; p 9 nodes = 5.82; p 50 = 0.56; p=0.01), and any nodal disease (HR=1.06 per involved node; p Conclusions: BCT yields favorable outcomes for the large majority of patients, although increased LR was observed among those with non-luminal A subtypes, younger age, and increasing lymph node involvement. Risk factors for LR following BCT appear to be converging with those following mastectomy in the current era. Citation Format: Braunstein LZ, Taghian AG, Niemierko A, Salama L, Capuco A, Wong JS, Punglia RS, Bellon JR, MacDonald SM, Harris JR. Breast cancer subtype, age and lymph node status as predictors of local recurrence following breast-conserving therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-04.