Lindsay L. Peterson

Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

PURPOSE Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. PATIENTS AND METHODS We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. RESULTS All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. CONCLUSION This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.

Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer

BackgroundAmong the solid tumors, human pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis. Gemcitabine is the standard first line of therapy for pancreatic cancer but has limited efficacy due to inherent or rapid development of resistance and combining EGFR inhibitors with this regimen results in only a modest clinical benefit. The goal of this study was to identify molecular targets that are activated during gemcitabine therapy alone or in combination with an EGFR inhibitor.MethodsPDAC cell lines were used to determine molecular changes and rates of growth after treatment with gemcitabine or an EGFR inhibitor, AG1478, by Western blot analysis and MTT assays respectively. Flow cytometric analysis was performed to study the cell cycle progression and rate of apoptosis after gemcitabine treatment. ShRNA was used to knockdown STAT3. An in vivo orthotopic animal model was used to evaluate STAT3 as a target. Immunohistochemical analysis was performed to analyze Ki67 and STAT3 expression in tumors.ResultsTreatment with gemcitabine increased the levels of EGFRTyr1068 and ERK phosphorylation in the PDAC cell lines tested. The constitutive STAT3Tyr705 phosphorylation observed in PDAC cell lines was not altered by treatment with gemcitabine. Treatment of cells with gemcitabine or AG1478 resulted in differential rate of growth inhibition. AG1478 efficiently blocked the phosphorylation of EGFRTyr1068 and inhibited the phosphorylation of down-stream effectors AKT and ERKs, while STAT3Tyr705 phosphorylation remained unchanged. Combining these two agents neither induced synergistic growth suppression nor inhibited STAT3Tyr705 phosphorylation, thus prompting further studies to assess whether targeting STAT3 improves the response to gemcitabine or AG1478. Indeed, knockdown of STAT3 increased sensitivity to gemcitabine by inducing pro-apoptotic signals and by increasing G1 cell cycle arrest. However, knockdown of STAT3 did not enhance the growth inhibitory potential of AG1478. In vivo orthotopic animal model results show that knockdown of STAT3 caused a significant reduction in tumor burden and delayed tumor progression with increased response to gemcitabine associated with a decrease in the Ki-67 positive cells.ConclusionsThis study suggests that STAT3 should be considered an important molecular target for therapy of PDAC for enhancing the response to gemcitabine.

Obesity and Cancer: Evidence, Impact, and Future Directions

BACKGROUND Mounting evidence, particularly from prospective epidemiologic studies but with additional support from animal models and mechanistic studies, supported conclusions in 2016 by the International Agency for Research on Cancer (IARC) in their review of the preventive effects of weight control on cancer risk. CONTENT The workgroup concluded that obesity is causally related to cancer at 13 anatomic sites (esophagus: adenocarcinoma; gastric cardia; colon and rectum; liver; gallbladder; pancreas; breast: postmenopausal; uterine endometrial; ovary; kidney: renal cell; meningioma; thyroid; and multiple myeloma). Further, avoiding weight gain and excess body fat will prevent cancer. Evidence on weight loss and reduction in risk of cancer is more limited. Ongoing clinical trials address the benefits of weight loss interventions after diagnosis. SUMMARY Here, we review the evidence from the 2016 IARC that obesity is causally related to cancer at 13 anatomic sites and identify areas for future research, including the consequences of childhood adiposity, the relation between velocity of weight gain and cancer risk, and improved methods for analysis of life-course adiposity and cancer risk. Refining understanding of mechanisms may further inform prevention strategies.

Association between renal function and chemotherapy-related toxicity in older adults with cancer

PURPOSE To evaluate the association between renal function (RF) and chemotherapy-related toxicity (CRT) in older adults with cancer and to compare the effect of different RF formulas and body weight measurements on this association. METHODS This is a secondary analysis of data from a prospective multicenter study of patients ≥ age 65 who were starting a new chemotherapy regimen. RF was estimated with 4 formulas (modified Jelliffe [Jelliffe], Cockcroft-Gault [CG], Wright, and Modification of Diet in Renal Disease [MDRD]), using actual, ideal and adjusted body weights for 492 patients. The association between baseline RF and grade 3-5 CRT was evaluated by unconditional logistic regression. RESULTS As a continuous variable, decreased creatinine clearance (CrCl) calculated by CG with actual body weight was associated with increased odds of CRT (OR 1.12, P<0.01; 95% CI 1.04-1.20) indicating that on average for every 10mL/min decrease in CrCl the odds of CRT increased by 12%. Very low RF (in the lowest 10%) with all formulas (CG, Jelliffe, Wright and MDRD) was associated with increased odds for CRT. This association is independent of the type of chemotherapy received (those requiring dose adjustment for renal function vs not). Neither primary dose reduction nor chemotherapy duration was associated with CRT. Serum creatinine alone was not associated with increased odds of CRT (OR 0.67, P=0.15). CONCLUSIONS Decreased RF is associated with increased odds of CRT and should be considered when assessing risk of CRT in older adults with cancer. Serum creatinine alone is not adequate for risk assessment.

A combined modality therapeutic approach to metastatic anal squamous cell carcinoma with systemic chemotherapy and local therapy to sites of disease: case report and review of literature

Cases of metastatic anal carcinoma managed with a combination of systemic chemotherapy and local therapies to both solitary sites of metastases and the primary site have been reported in the literature. We present a case of a 55-year-old male with metastatic anal squamous cell carcinoma to the liver treated with induction chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5FU) followed by liver resection and radiation to the anal primary with concurrent 5FU and mitomycin. This approach resulted in control of disease without evidence of recurrence, and no increased toxicities now 19 months from initial diagnosis to time of reporting. This novel approach resulted in a good treatment response as documented by imaging and symptom improvement and a long disease free interval.

Genetic markers of immunoglobulin G and immunity to cytomegalovirus in patients with breast cancer

Human cytomegalovirus (CMV), a ubiquitous herpesvirus, has been implicated in the etiology of breast cancer. It is clear that not all people exposed to CMV are equally likely to develop this malignancy, implying the presence of host genetic factors that might modulate the cancer-spurring properties of the virus. CMV has evolved sophisticated strategies for evading host immunosurveillance. One strategy involves encoding decoy Fcγ receptors (FcγR) that thwart the Fcγ-mediated effector functions, such as antibody-dependent cellular cytotoxicity. In this investigation, using an enzyme-linked immunosorbent assay (ELISA), we aimed to determine whether the decoy FcγR encoded by the CMV gene RL13 binds differentially to anti-CMV antibodies expressing different immunoglobulin GM (γ marker) allotypes, genetic markers of immunoglobulin G (IgG). Results of our ELISA binding studies showed that the absorbance values for the binding of the viral FcγR to the GM 17-expressing IgG antibodies were significantly higher than for the GM 3-expressing antibodies (0.60 vs. 0.36; p=0.0019). These findings provide mechanistic insights into the modulating role played by the genetic variants of IgG in the generation of immunity to CMV in patients with breast cancer.

Chapter Two – Disparities in Obesity, Physical Activity Rates, and Breast Cancer Survival

Abstract The significantly higher breast cancer (BCa) mortality rates of African‐American (AA) women compared to non‐Hispanic (NHW) white women constitute a major US health disparity. Investigations have primarily focused on biological differences in tumors to explain more aggressive forms of BCa in AA women. The biology of tumors cannot be modified, yet lifestyle changes can mitigate their progression and recurrence. AA communities have higher percentages of obesity than NHWs and exhibit inefficient access to care, low socioeconomic status, and reduced education levels. Such factors are associated with limited healthy food options and sedentary activity. AA women have the highest prevalence of obesity than any other racial/ethnic/gender group in the United States. The social ecological model (SEM) is a conceptual framework on which interventions could be developed to reduce obesity. The SEM includes intrapersonal factors, interpersonal factors, organizational relationships, and community/institutional policies that are more effective in behavior modification than isolation from the participants’ environmental context. Implementation of SEM‐based interventions in AA communities could positively modify lifestyle behaviors, which could also serve as a powerful tool in reducing risk of BCa, BCa progression, and BCa recurrence in populations of AA women.

Systemic capillary leak syndrome in a patient receiving adjuvant oxaliplatin for locally advanced colon cancer

Colorectal cancer is the third most common cancer diagnosed in the USA each year. Oxaliplatin, a platinum-based chemotherapy agent, is part of the standard adjuvant chemotherapy regimen FOLFOX (oxaliplatin with 5-fluorouracil [5-FU] and leucovorin [LV]) for the treatment of stage III and some high-risk stage II colorectal cancers. Although oxaliplatin is generally well tolerated, certain side effects such as nausea, vomiting, and peripheral neuropathy are common. We report a case of oxaliplatin-induced capillary-leak syndrome in a 63-year-old man undergoing his 12th and final cycle of FOLFOX for stage III colorectal cancer. To our knowledge, this is the first case of systemic capillary leak syndrome (SCLS) reported in association with oxaliplatin. Currently, there is no prevention for SCLS. Documenting future cases of SCLS attributed to oxaliplatin is vital, as SCLS is associated with significant morbidity and mortality and no standard treatments beyond supportive care measures exist. Early recognition and diagnosis are therefore essential to improving patient outcomes.

The Plausibility of Obesity Paradox in Cancer—Point

In contrast to the convincing evidence that obesity (measured by body mass index, BMI) increases the risk of many different types of cancer, there is an ambiguity in the role of obesity in survival among cancer patients. Some studies suggested that higher BMI decreased mortality risk in cancer patients, a phenomenon called the obesity paradox. The spurious positive association between BMI and cancer survival is likely to be explained by several methodologic limitations including confounding, reverse causation, and collider stratification bias. Also, the inadequacy of BMI as a measure of body fatness in cancer patients commonly experiencing changes in body weight and body composition may have resulted in the paradox. Other factors contributing to the divergent results in literature are significant heterogeneity in study design and method (e.g., study population, follow-up length); time of BMI assessment (pre-, peri-, or post-diagnosis); and lack of consideration for variability in the strength and directions of associations by age, sex, race/ethnicity, and cancer subtype. Robust but practical methods to accurately assess body fatness and body compositions and weight trajectories in cancer survivors are needed to advance this emerging field and to develop weight guidelines to improve both the length and the quality of cancer survival. Cancer Res; 78(8); 1898-903. ©2018 AACR.

Physical Activity and Breast Cancer: an Opportunity to Improve Outcomes

Purpose of ReviewTo review current data regarding physical activity and breast cancer including cancer risk, cancer prognosis, treatment-related side effects, and patient-reported outcomes. We will summarize current physical activity guidelines for cancer survivors and discuss opportunities to study and implement physical activity programs in cancer survivors.Recent FindingsObservational evidence suggests that physical activity is associated with a reduced risk of developing breast cancer, a reduced risk of breast cancer recurrence, and improved breast cancer-specific and all-cause mortality. Studies also show that physical activity improves factors important to quality of life such as chemotherapy-related fatigue and the aromatase inhibitor-induced musculoskeletal syndrome.SummaryPhysical activity is an important component of breast cancer survivorship. Challenges exist in conducting clinical trials of physical activity and implementing current guidelines, yet there are significant opportunities to advance the field through translational research efforts and utilization of available community resources.