Katarzyna J. Jerzak

A network meta-analysis of the sequencing and types of systemic therapies with definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LASCCHN)☆.

OBJECTIVES The current standard therapy for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) is platinum-based chemotherapy plus concurrent radiotherapy (CRT), but several systemic therapies have been evaluated. We performed a Bayesian network meta-analysis (NMA) with random effects to enable direct and indirect comparisons of all existing treatment modalities for LASCCHN simultaneously. MATERIAL AND METHODS A systematic review was conducted using MEDLINE, EMBASE, ASCO abstracts, ASTRO abstracts and the Cochrane Central of Registered Trials using Cochrane methodology to identify randomized controlled trials (RCTs) up to June 2016. Only abstracts that involved the same definitive radiotherapy in the arms for the RCT were included. RESULTS Sixty-five RCTs involving 13,574 patients and 16 different treatment strategies were identified. Chemotherapy plus concurrent radiation (CRT) was superior to RT with a HR of 0.74 (95%CR 0.69-0.79) for OS in the NMA. Only 3 trials compared RT alone to concurrent therapy with an EGFR antibody (ERT), demonstrating a superior OS (HR 0.75, 95% CR 0.60-0.94), but this difference was not statistically significant when interpreted in a NMA (HR 0.84, 95%CR 0.65-1.08). ERT was not superior to CRT (HR 1.19, 95%CR 0.93-1.54), and the addition of neo-adjuvant taxane-based chemotherapy to CRT was not beneficial (HR 0.86, 95% CR 0.70-1.07). CONCLUSION The addition of either adjuvant or neoadjuvant chemotherapy to the CRT backbone does not confer an OS benefit in the treatment of LASCCHN. Similarly, ERT does not confer an OS benefit for patients who are eligible for CRT.

Cetuximab plus irinotecan versus panitumumab in patients with refractory metastatic colorectal cancer in Ontario, Canada

The addition of irinotecan to an epidermal growth factor receptor (EGFR) antibody has previously been shown to improve tumor response rate and time to progression but not overall survival (OS) for refractory metastatic colorectal cancer (mCRC). We assessed the “real‐world” effectiveness and toxicity of the combination versus monotherapy. In Ontario, Canada, universal public funding is available for either cetuximab plus irinotecan (Cmab + I) combination therapy or panitumumab (Pmab) monotherapy, only in patients with refractory nonmutated RAS mCRC. All patients diagnosed before December 2012 and treated with an EGFR antibody for mCRC were identified from the Ontario drug database and linked to the Ontario Cancer Registry and other administrative databases to ascertain baseline characteristics, health services utilization, and outcomes. Multivariable Cox and logistic models were constructed to compare the time to treatment discontinuation (TTD), OS, emergency department (ED) or hospital visits between Cmab + I and Pmab. Observable confounders were adjusted for using propensity score methods. One thousand and eighty‐one patients were identified (Cmab + I: 278, Pmab: 803). Patients receiving Cmab + I were younger (mean age 61 vs 64 years) and had a longer duration of prior irinotecan treatment. The use of Cmab + I as compared to Pmab alone was associated with a prolonged TTD [median: 3.8 months vs 2.8 months] and an improved OS [median: 8.8 months vs. 5.9 months] with an adjusted HR of 0.62 [95% CI 0.53–0.73, p < 0.001]. Both treatment regimens afforded similar 14‐day mortality and incidence of ED or hospital visits. The findings for patients over and below the age of 65 were similar.

Targeted metabolomics in colorectal cancer: a strategic approach using standardized laboratory tests of the blood and urine

Background Glycolytic markers have been detected in colorectal cancer (CRC) using advanced analytical methods. Methods Using commercially available assays, by-products of anaerobic metabolism were prospectively measured in the blood and urine of 20 patients with metastatic colorectal cancer (mCRC) and 20 patients with local disease. Twenty-four-hour urine citrate, plasma lactate, ketones, venous blood gas, anion gap, and osmolar gap were investigated. Results of patients with metastatic and local CRC were compared using two-sample t-tests or equivalent nonparametric tests. In addition, plasma total CO2 concentrations in our local hospital (5,931 inpatients and 1,783 outpatients) were compared retrospectively with those in our dedicated cancer center (1,825 outpatients) over 1 year. Results The average venous pCO2 was higher in patients with mCRC (50.2 mmHg; standard deviation [SD]=9.36) compared with those with local disease (42.8 mmHg; SD=8.98), p=0.045. Calculated serum osmolarity was higher in mCRC and attributed to concomitant sodium and urea elevations. In our retrospective analysis, plasma total CO2 concentrations (median=27 mmol/L) were higher in cancer patients compared to both hospital inpatients (median=23 mmol/L) and outpatients (median=24 mmol/L), p<0.0001. Conclusion Patients with mCRC had higher venous pCO2 levels than those with local disease. Although causation cannot be established, we hypothesize that pCO2 elevation may stem from a perturbed metabolism in mCRC.

Prevention of carboplatin-induced hypersensitivity reactions in women with ovarian cancer:

Background Carboplatin-based chemotherapy offers high response rates and improved overall survival for women with epithelial ovarian cancer, but its use is limited by the occurrence of hypersensitivity reactions. To evaluate the efficacy of prophylactic diphenhydramine for hypersensitivity reaction prevention, we reviewed the incidence of hypersensitivity reactions and identified patients at high risk of hypersensitivity reactions. Methods Women receiving ≥6 cycles of carboplatin-based chemotherapy for epithelial ovarian cancer were identified from our institutional database at the Princess Margaret Cancer Centre. Institutional policy was changed in 2009 to introduce diphenhydramine prophylaxis for patients receiving ≥6 cycles of carboplatin. Additional clinical data were abstracted from the patient record. Results Between 2006 and 2012, 450 women received ≥6 cycles of carboplatin-based chemotherapy for epithelial ovarian cancer. Two hundred and ninety-one women received prophylaxis with diphenhydramine. Carboplatin-induced hypersensitivity reactions occurred in 41 of 449 patients (9%). Univariable predictors of carboplatin-induced hypersensitivity reactions included administration of 8 to 10 cycles of carboplatin, history of other drug allergies and a platinum-free interval >12 months. BRCA mutational status was not predictive. In a multivariable analysis, the number of cycles of carboplatin and a platinum-free interval >12 months were independent predictors of hypersensitivity reactions. There was a trend towards diphenhydramine prophylaxis reducing the incidence of hypersensitivity reactions in women with a platinum-free interval compared to continuous delivery; this was most marked when the platinum-free interval was >12 months (n = 64) (OR: 0.2 (95% CI: 0.046–0.83), p = 0.03). Conclusions The administration of diphenhydramine to women who have a platinum-free interval may reduce the risk of hypersensitivity reaction, but prospective evaluation is required.

An update on adjuvant systemic therapy for elderly patients with early breast cancer

ABSTRACT Introduction: Elderly women with early breast cancer require an individualized approach to risk assessment and treatment. Unfortunately, there are limited data to inform optimal adjuvant therapy decisions in this population. Cytotoxic chemotherapy, biologic treatments and endocrine agents, while important in reducing breast cancer recurrence and mortality, are associated with the potential for adverse effects that may be of particular significance to elderly patients. Areas covered: In this review, we summarize the evidence for geriatric assessment in elderly patients with early breast cancer, outline special considerations for the use of chemotherapy and trastuzumab in older adults, and describe the age-specific risks of endocrine therapy in the adjuvant breast cancer setting. Expert opinion: The treatment of elderly women with early breast cancer should take into account cancer risk, life expectancy, comorbidities, functional status, physiologic changes, and patient values. Formal geriatric assessment may better inform treatment recommendations for individual patients. In general, there is no strong evidence to suggest that older women benefit less from standard adjuvant therapies than do their younger counterparts. When choosing between endocrine therapies, the differential risks associated with each agent should be considered and particular attention to the fracture risk on aromatase inhibitors (AIs) is warranted. Enrolment of women over 70 years of age into breast cancer clinical trials should be encouraged to better inform treatment guidelines.

An update on treatment for post-menopausal metastatic breast cancer in elderly patients

ABSTRACT Introduction: Elderly patients make up a significant proportion of patients with metastatic breast cancer. With several options available in the metastatic setting for hormone positive breast cancer, these patients require an individualized approach to decision-making that considers multiple factors beyond performance status and chronologic age. Areas covered: The authors review the literature on endocrine monotherapy and combinations for hormone positive metastatic breast cancer, with specific commentary on the efficacy and toxicity for elderly patients. The authors describe the role of comprehensive geriatric assessment (CGA) and highlight the considerations for the use of bone modifying agents, and HER2-targeted therapy for hormone positive/HER2+ patients. Expert opinion: Evidence for elderly patients is largely based on subgroup analyses, which should be interpreted with caution. Nonetheless, elderly patients with metastatic hormone receptor positive breast cancer appear to derive similar benefit from treatments as younger patients. Similarly, for most drugs, these patients have no significant worsening of toxicity compared to younger patients. In addition to tumor biology, patient values and information from the CGA should be used to guide treatment decisions.

Ataxia–telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review

Background Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. Methods In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy. Results Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic ATM variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. For women in this group who have a strong family history of breast cancer, earlier screening with both magnetic resonance imaging and mammography should be considered. High-quality data to inform the management of established breast cancer in carriers of pathogenic ATM variants are lacking. Although deficiency in the ATM gene product might confer sensitivity to dna-damaging pharmaceuticals such as inhibitors of poly (adp-ribose) polymerase or platinum agents, prospective clinical trials have not been conducted in the relevant patient population. Furthermore, the evidence with respect to radiation therapy is mixed; some data suggest increased toxicity, and other data suggest improved clinical benefit from radiation in women who are carriers of a pathogenic ATM variant. Conclusions As in the 2017 U.S. National Comprehensive Cancer Network guidelines, we recommend high-risk imaging for women in Ontario who are heterozygous for a pathogenic ATM variant. Currently, ATM carrier status should not influence decisions about systemic or radiation therapy in the setting of an established breast cancer diagnosis.

Does adjuvant radiation therapy benefit women with small mammography-detected breast cancers?

BACKGROUND Women with small nonpalpable breast tumours have an excellent prognosis. The benefit of radiotherapy in this group of low-risk women is unknown. METHODS A cohort of 1595 women with stages i-iii invasive breast cancer treated with breast-conserving surgery were followed for local recurrence. Using t-tests, baseline demographic data and tumour characteristics were compared for the women who had palpable (n = 1023) and mammography-detected (n = 572) breast cancers. The 15-year actuarial risk of local recurrence was estimated using a Kaplan-Meier method, stratified for adjuvant radiation therapy (yes or no), tumour palpability (palpable or not), and tumour size (≤1 cm or >1 cm). Hazard ratios (hrs) and 95% confidence intervals (95% cis) were calculated using a multivariate Cox regression model. Results were considered statistically significant if 2-tailed p values were less than 0.05. RESULTS Among women with a nonpalpable tumour, the 15-year actuarial rates of local recurrence were, respectively, 13.9% and 18.3% for those treated and not treated with adjuvant radiation therapy (hr: 0.65; 95%ci: 0.40 to 1.06; p = 0.08). Among women with small nonpalpable breast cancers (≤1.0 cm), the rates were 14.6% and 13.4% respectively (p = 0.67). The absolute reduction in 15-year local recurrence was 11.0% for women with palpable tumours. CONCLUSIONS Our results suggest that women with small (<1 cm) screen-detected nonpalpable breast cancers likely derive little benefit from adjuvant radiotherapy; however, an adequately powered randomized trial would be required to make definitive conclusions.

Abstract 3787: Thyroid hormone induced proliferation of breast cancer cell lines: A novel approach to hormone therapy

Introduction: The thyroid hormone (TH) pathway influences cell growth and it may be a novel target for breast cancer (BC) therapy. However, various TH receptor (THR) isoforms exist and some have opposing functions thus complicating the role of THs in BC. Our previous work suggests that THR alpha1 (THRα1) promotes TH-mediated BC proliferation. Here we offer a mechanism that explains these findings. We first evaluated the role of THs on BC cell line proliferation using escalating doses of tri-iodothyronine (T3) and thyroxine (T4). Next, propylthiouracil (PTU) was used to block T4 conversion to T3 demonstrating that observed proliferation was TH dependent. Finally, the anti-proliferative efficacy of a THRα1 inhibitor, dronedarone, was used to demonstrate the necessity of THRα1 downstream of TH signalling. Dronedarone was selected because it is an FDA approved anti-arrhythmic drug, which may also serve as a novel anti-cancer agent. Methods: The effect of increasing concentrations of T3 and T4 on the proliferation of 3 BC cell lines (MCF 7, MD-MB-231, BT-474) in 10% charcoal-stripped phenol-free serum were evaluated at 24 and 48 hours following standard MTT-assay protocols. Increasing doses of PTU and dronedarone were added to cells with 200uM T3 or T4 to measure proliferation of MCF-7 and MD-MB-231 cells using MTT assays. Results: There was a statistically significant increase in the proliferation of MCF7, MD-MB-231 and BT-474 cells with the addition of T3 and T4 at 24 and 48 hours in a dose dependent manner. Of note, BT-474 cells had a significantly slower proliferation rate and required 9 days of incubation prior to detection of proliferation. The addition of PTU reduced proliferation by 50% in MCF7 and MD-MB-231 cells in the presence of T4 at roughly 5 mM compared to the presence of T3 which had an IC50 of 12mM. This shows that TH signalling is mediated by T4 conversion to T3 in these cell lines. PTU alone reduced cell proliferation by 50% at concentrations above 12 mM, suggesting that PTU may also act through other mechanisms. Cell proliferation was not affected by the presence of dronedarone alone, but the combination of 10μM dronedarone and T3 or T4 significantly reduced proliferation of both MCF7 and MD-MB-231 cells. These results suggest that THRα1 is required for TH mediated cell proliferation. A library of compounds similar in structure to dronedarone is being designed to offer additional candidates for more potent THRα1 inhibition. The properties and structures of these novel compounds will be presented. Conclusion: The proliferation of several BC cell lines increases in response to exogenous T3 and T4 when grown in hormone depleted growth media. These results demonstrate the role of specific events contributing to TH-mediated cell proliferation, including T4 conversion to T3 and the necessity of downstream THRα1. Ultimately, in conjunction with our previous work, we propose that THRα1 inhibition is a novel target for cancer therapy. Citation Format: Katarzyna Joanna Jerzak, Jessica G. Cockburn, John Hassel, Kathleen I. Pritchard, Sukhbinder K. Dhesy-Thind, Bane Anita. Thyroid hormone induced proliferation of breast cancer cell lines: A novel approach to hormone therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3787.

COGNITIVE SEQUELAE OF ADJUVANT ENDOCRINE THERAPY FOR THE TREATMENT OF BREAST CANCER IN OLDER WOMEN: A FEASIBILITY STUDY

The Women Gender Sex and Dementia (WGSD) cross-cutting program was created to ensure that all CCNA teams integrate sex/ gender in their dementia research examining disease etiology, symptoms and progression as well as quality of life of those with the disease in their human or animal studies. Methods: In April and October 2015, CCNA team leaders were surveyed to describe new knowledge and advances they made to address sex/gender research challenges and gaps within their research. Between April and October, WGSD members carried out interviews with team leads to motivate greater emphasis on sex/gender research related to dementia. We classified teams’ responses into three categories: 1) No response, 2) Sex/gender included as a covariate in data analysis, 3) Planned studies with a specific focus on sex and/or gender were described. Results:Across the two reporting periods, we found a decrease from 75% to 50% in the number of teams providing either no response or simply stating they would conduct covariate analysis and a corresponding increase from 25% to 50% in the number who described planned analysis for sex and gender in their research. Conclusions:Discussion with WGSD team members led to a major increase in the initiation of sex and gender focused research within the teams. However, this work needs to be sustained and there is additional work that is required to support the remaining teams who either have not responded to the directive or who have no specific planned research apart from including sex and gender as covariates. WGSD will continue to monitor the trend that direct emphasis on sex/gender by program leads will result in concrete increase in planned sex/gender studies. We anticipate that each year new researchers who did not previously investigate sex and gender will present and publish their findings which were made possible through funding provided by the Institute of Gender and Health and the Women’s Brain Health Initiative.