Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients.

PURPOSE: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer. METHODS: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia. RESULTS: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia. CONCLUSIONS: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

Quality of written feedback given to medical students after introduction of real-time audio monitoring of clinical encounters.

BACKGROUND: Direct observation is necessary for specific and actionable feedback, however clinicians often struggle to integrate observation into their practice. Remotely audio-monitoring trainees for periods of time may improve the quality of written feedback given to them and may be a minimally disruptive task for a consultant to perform in a busy clinic. METHODS: Volunteer faculty used a wireless audio receiver during the second half of students' oncology rotations to listen to encounters during clinic in real time. They then gave written feedback as per usual practice, as did faculty who did not use the listening-in intervention. Feedback was de-identified and rated, using a rubric, as strong/medium/weak according to consensus of 2/3 rating investigators. RESULTS: Monitoring faculty indicated that audio monitoring made the feedback process easier and increased confidence in 95% of encounters. Most students (19/21 respondents) felt monitoring contributed positively to their learning and included more useful comments. 101 written evaluations were completed by 7 monitoring and 19 non-monitoring faculty. 22/23 (96%) of feedback after monitoring was rated as high quality, compared to 16/37 (43%) (p < 0.001) for monitoring faculty before using the equipment (and 20/78 (26%) without monitoring for all consultants (p < 0.001)). Qualitative analysis of student and faculty comments yielded prevalent themes of highly specific and actionable feedback given with greater frequency and more confidence on the part of the faculty if audio monitoring was used. CONCLUSIONS: Using live audio monitoring improved the quality of written feedback given to trainees, as judged by the trainees themselves and also using an exploratory grading rubric. The method was well received by both faculty and trainees. Although there are limitations compared to in-the-room observation (body language), the benefits of easy integration into clinical practice and a more natural patient encounter without the observer physically present lead the authors to now use this method routinely while teaching oncology students.

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Dose dense MVAC prior to radical cystectomy: a real-world experience.

PURPOSE: Our primary endpoint was to assess pathological response rate (pT0N0 and ≤pT1N0) for patients with BCa treated with the accelerated or dose dense MVAC (ddMVAC) chemotherapy followed by radical cystectomy (RC) in this real-word multi-institutional cohort. MATERIALS AND METHODS: We retrospectively reviewed records of patients with urothelial cancer who underwent ddMVAC and RC at seven contributing institutions from 2000 to 2015. Patients with cT2-4a, M0 BCa were included. Presence of cT3-4 disease, hydronephrosis, lymphovascular invasion and/or existence of sarcomatoid, or micropapillary features on the initial transurethral resection of bladder tumor specimen was defined as high-risk disease. Logistic regression models for prediction of pT0N0 and ≤pT1N0 were generated for the entire cohort as well as for the cN0 subgroup. The multivariable Cox proportional hazards regression model for survival using post RC data was used to assess hazard ratios (HRs) for the variables of interest. RESULTS: A total of 345 patients received ddMVAC chemotherapy during the study period; 85% had high-risk features. The median number of chemotherapy cycles was 4 (IQR 4-4); >90% of patients completed all scheduled cycles. The observed rates of pT0N0 and ≤pT1N0 were 30.4 and 49.3%, respectively, among cN0 patients. On the multivariable regression model, the presence of more than one clinical high-risk element was associated with 70% [OR 0.30 95% CI (0.10-0.86); p = 0.02] reduction in the odds of achieving partial pathological response. CONCLUSIONS: A complete response (pT0N0) was observed in one-third of patients after neoadjuvant ddMVAC therapy, and a partial response (≤pT1N0) was observed in nearly half of the cases in this real-world experience with this regimen. To our knowledge, this represents the largest experience outside clinical trial settings.

Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer.

In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484).

CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy.

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.

Early experience with chemotherapy intensification for poor-prognosis metastatic germ cell cancer and unfavorable tumor marker decline.

INTRODUCTION: Intensified chemotherapy improved outcomes for men with poor-prognosis metastatic germ cell cancer (GCC) and unfavorable tumor marker decline after one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in the GETUG-13 trial. Herein, we report our experience to date using a similar approach. METHODS: Patients were identified from our electronic GCC database. Men with poor-prognosis GCC and unfavorable tumor marker decline were offered intensified chemotherapy consisting of T-BEP (three cycles) plus paclitaxel, ifosfamide, and cisplatin (TIP) (one cycle), along with prophylactic granulocyte-colony stimulating factor (G-CSF) and resection of residual masses. Cisplatin, etoposide, and ifosfamide (PEI) replaced the last cycle of T-BEP for bleomycin pulmonary concerns. Serious toxicities, progression-free survival, and overall survival were evaluated retrospectively. RESULTS: Ten patients with poor-prognosis GCC were identified from May 2012 to April 2016. Eight patients had unfavorable tumor marker decline. Six were offered and received intensified chemotherapy (two T-BEPx3 + TIP and four T-BEPx2 + PEI + TIP). Serious toxicities included neutropenic sepsis, deep venous thrombosis, and C. difficile colitis, but there were no toxic deaths. One patient died of synchronous metastatic adenocarcinoma ex teratoma. The remaining five patients achieved marker-negative partial response, two had residual mature teratoma excised, and four have no evidence of disease after surgery. All are alive at a median of 63.5 months (range 46.3-65.6); one patient has grade 2 peripheral sensory neuropathy, and one patient has grade 2 cognitive disturbance. Of four patients treated with standard BEP, two have died of disease and two are alive at 51.4 and 53.6 months. CONCLUSIONS: Our experience with intensified chemotherapy for men with poor-prognosis GCC and unfavorable tumor marker decline confirms that it is feasible, reasonably safe, and appears to provide results similar to those reported in GETUG-13.

Prostate Cancer Lymphangitic Pulmonary Carcinomatosis: Appearance on 18F-FDG PET/CT and 18F-DCFPyL PET/CT.

A 51-year-old man diagnosed with high-grade, high-volume metastatic castration-sensitive prostate adenocarcinoma received pelvic radiation, androgen deprivation therapy, and intravenous docetaxel. Serum prostate-specific antigen became undetectable following treatment. Within a year, his cancer progressed to castration-resistant disease, and he was treated with oral abiraterone acetate 1000 mg and prednisone 10 mg daily. Despite this, the serum prostate-specific antigen rose from 0.03 to 1.39 µg/L, and F-DCFPyL and F-FDG PET/CT showed progression. While F-DCFPyL uptake may be seen in aggressive disease, F-FDG portends poor prognosis. Despite intravenous platinum-based chemotherapy, the patient died of respiratory failure 20 months after his initial diagnosis.

Hormone-refractory prostate cancer: a primer for the primary care physician.

OBJECTIVE: To provide a current and evidence-based clinical review of practical value to primary care physicians encountering men with hormone-refractory prostate cancer (HRPC) in their practice. METHODS: Evidence-based narrative review by two expert clinicians incorporating results of systematic reviews and randomized trials whenever available. RESULTS: HRPC represents the final common pathway to death from prostate adenocarcinoma, the single most prevalent cancer in Canadian men. However, primary care physicians will not encounter these patients with a frequency adequate to develop confidence in their care. HRPC is defined by progressive disease despite castration, and biologically is a characterized by androgen hypersensitivity. It is important to understand that HRPC is a disease spectrum ranging from asymptomatic patients with only a rising prostatic-specific antigen (PSA) level and a prognosis measured in years to extremely symptomatic patients with widespread metastases requiring end-of-life care. Numerous effective management options are now available for HRPC and are selected based on the phase of the disease natural history, and patient comorbidities and preferences. CONCLUSIONS: Men with HRPC have therapeutic options that can improve and maintain both the quality and quantity of their lives. A co-management approach including a medical oncologist and the patient's urologist and primary care physician is preferred.

A randomized phase II study of pelareorep and docetaxel or docetaxel alone in men with metastatic castration resistant prostate cancer: CCTG study IND 209.

BACKGROUND: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has in vitro synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel. PATIENTS AND METHODS: In this randomized, open-label phase II study, patients received docetaxel 75mg/m2 on day 1 of a 21-day cycle and prednisone 5mg twice daily, in combination with pelareorep (arm A) or alone (arm B). The primary endpoint was 12 weeks lack of disease progression rate (LPD). RESULTS: Eighty-five pts were randomized. Median age was 69, ECOG performance status was 0/1/2 in 31%/66%/3% of patients. Bone/regional lymph node/liver metastases were present in 98%/24%/6%. The median prognostic score was slightly higher in Arm A (144 vs. 129 p= 0.005). Adverse events were as expected but more prevalent in arm A. The 12-week LPD rate was 61% and 52.4% in arms A/B (p=0.51). Median survival was 19.1 on Arm A and 21.1 months on Arm B (HR 1.83; 95% CI 0.96 to 3.52; p=0.06). No survival benefit of pelareorep was found. CONCLUSION: Pelareorep with docetaxel was tolerable with comparable LPD in both arms but response and survival were inferior and so this combination does not merit further study.

Chemoradiotherapy in octogenarians as primary treatment for muscle-invasive bladder cancer.

INTRODUCTION: While radical cystectomy is the gold standard for muscle-invasive bladder cancer (MIBC), in octogenarians cystectomy results in a higher perioperative mortality rate (6.8-11.1%) than in younger patients (2.2%). Trimodality therapy is a bladder-sparing regimen composed of transurethral resection of bladder tumour (TURBT) and chemoradiotherapy, with intent for salvage cystectomy, and has a 62.5-90% initial complete response rate. In this study, we evaluate TURBT and chemoradiotherapy without salvage cystectomy in medically inoperable octogenarian patients. METHODS: We identified a retrospective cohort of patients aged 80-89 years with invasive urothelial carcinoma who received combination chemoradiotherapy between 2008 and June 2014. Outcomes were evaluated by Kaplan-Meier (KM) and Cox regression. RESULTS: In 40 patients, the mean age was 84.5 years (interquartile range [IQR] 83-86). Seventeen patients received hypofractionated, low-dose radiotherapy (LD) (37.5-40 Gy), while 23 received conventionally fractionated radiotherapy (high-dose [HD]) (50-65 Gy). Mean overall survival (OS) was 20.7 months (IQR 12.75-23.25), while mean recurrence-free survival (RFS) was 13.75 months (IQR 3.75-16.5). Patients receiving HD radiotherapy showed improved OS and local RFS (LRFS) without significant differences in Grade 3-4 toxicities. Univariate Cox regression identified hydronephrosis as a predictor of worse OS and local recurrence and HD radiotherapy as a predictor of improved OS and local recurrence rates. Multivariate Cox regression identified hydronephrosis to be a significant predictor of LRFS. CONCLUSIONS: Primary chemoradiotherapy for inoperable patients with MIBC resulted in a three-year OS of 54.9% (comparable to cystectomy) and three-year RFS of 42.3%. Superior outcomes were associated with more aggressive chemoradiotherapy treatment. The results of the local control subanalyses in this study are hypothesis-generating due to the limited patient numbers in the cohort.

Concurrent Neoadjuvant Chemotherapy and Radiation Therapy in Locally Advanced Breast Cancer.

PURPOSE: To evaluate whether concurrent neoadjuvant radiation added to standard chemotherapy could increase the pathologic complete response (pCR) to treatment for locally advanced breast cancer (LABC). METHODS AND MATERIALS: This prospective phase 2 trial recruited 32 LABC patients from 2009 to 2011. Patients received neoadjuvant every-3-weekly 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) for 3 cycles, followed by weekly docetaxel (35 mg/m2) for 9 cycles. Regional radiation (45 Gy/25 plus 5.4 Gy/5) was delivered concurrently with docetaxel, then modified radical mastectomy. Patients were matched post hoc by a blinded statistician to a concurrent cohort treated with neoadjuvant chemotherapy, modified radical mastectomy, and adjuvant regional radiation. RESULTS: Thirty of 32 patients completed treatment. Twenty-seven were successfully matched by propensity score to 81 control patients by age, stage, and molecular subtype. The concurrent chemoradiation produced a significant increase in pCR (14% vs 22%, P<.001) but no statistically significant difference in disease-free and overall survival at 3 years (respectively, 69% vs 81%, P=.186, hazard ratio 0.51; and 74% vs 89%, P=.162, hazard ratio 0.46). Toxicity included 25% of patients with grade 3 pneumonitis and 25% of patients with dermatitis, and 1 death. CONCLUSIONS: Concurrent neoadjuvant radiation added to radiosensitizing chemotherapy significantly improved pCR. A prospective randomized clinical trial is warranted to exploit the improved response seen with concurrent therapy but using another radio-sensitizing taxane, to better minimize treatment-related toxicity and determine its impact on overall survival.

A Single Institution Consensus on the Use of Sequential or Concurrent Hormonal Therapy for Breast Cancer Patients Receiving Radiation Therapy.

BACKGROUND AND OBJECTIVES: For hormone-sensitive breast cancers, treatment with breast-conserving surgery, tamoxifen, or aromatase inhibitors, along with adjuvant radiation, is the mainstay of therapy. The ideal timing of hormonal and radiation treatment is not well defined, and there is a significant degree of practice variability between concurrent and sequential treatment regimes. This variability can cause confusion amongst the clinical team resulting in contradictory recommendations, loss of patient trust, and the potential for missed initiation of hormonal therapy. METHODS: To address this question, a systematic review of the literature was conducted and presented to the breast cancer multidisciplinary team at the London Regional Cancer Center. A three-round modified Delphi method was used to obtain a consensus on a series of a priori determined statements. RESULTS: With the currently available evidence, the consensus was that hormonal therapy should be given sequentially after radiation. This will limit potential overlapping adverse effects between hormonal therapy and radiation that may decrease completion of treatment. The sequential approach has not been associated with any harm in clinical outcomes, and there is some suggestion of increased toxicity with concurrent use. However, in patients at high risk of distant recurrence, they felt it would be reasonable to consider concurrent treatment to avoid any delay in therapy. CONCLUSION: The consensus of our institution to utilize a sequential approach will standardize the treatment decisions and reduce the risk of failing to initiate hormonal therapy. Despite the lack of level 1 evidence, the Delphi methodology did provide a high level of confidence for our group to choose the sequential approach. The consensus was developed after a review of the literature revealed that there was no clear superiority of one schedule over the other and evidence that concurrent treatment may increase adverse events.

Concurrent or Sequential Hormonal and Radiation Therapy in Breast Cancer: A Literature Review.

BACKGROUND AND OBJECTIVES: Adjuvant hormonal therapy is frequently used in the treatment of women with estrogen receptor (ER)/progesterone receptor (PR) positive breast cancer. When radiotherapy is given, hormone therapy may be delivered in a concurrent or sequential manner. Hormonal blockade with tamoxifen or aromatase inhibitors is thought to arrest hormonally dependent cancer cells in the early G1 phase of the cell cycle. This has been theorized to reduce the efficacy of radiation, which is known to be more effective in cells that are actively dividing. Therefore, there has been a reluctance by many to treat with concurrent hormonal and radiation therapy. METHODS: We performed a search of the Medline database that led to the identification of 39 studies. Abstract and full-text review of these studies led to the identification of seven English non-review studies in peer-reviewed literature between 1995 and 2015 that addressed the question of timing of radiation and hormonal therapy. Outcome measures were captured from each of the studies. RESULTS: No difference in survival or local-regional recurrence was identified between concurrent versus sequential treatment. Furthermore, no difference in cosmetic outcome or adverse effects was noted for either approach. However, when comparing radiation alone or radiation and hormonal therapy, there was an increased risk of breast and lung fibrosis with combined treatment. CONCLUSIONS: Hormone therapy, concurrent or sequential, with radiation results in comparable disease-related outcomes, including survival and recurrence. However, given the theoretical reduction in efficacy and increased rates of fibrosis with concurrent use, it is reasonable to support the use of sequential therapy.

ECF chemotherapy for liver metastases due to castration-resistant prostate cancer.

INTRODUCTION: Most men with metastatic castration-resistant prostate cancer (CRPC) have biochemical response to docetaxel, but the objective response rate is low. Liver metastases are uncommon with CRPC and associated with shorter survival. More active treatment might benefit these patients. Epirubicin, cisplatin and flurouracil (ECF) is a standard regimen for gastric cancer and response in CRPC liver metastases has been reported. We reviewed our experience with ECF in CRPC with the primary objective of determining its anti-tumour activity in patients with liver metastatic CRPC. METHODS: Men with CRPC treated with ECF were identified from electronic databases and data were extracted from medical records. Men with tumours showing neuroendocrine features were excluded. RESULTS: In total, we identified 14 CRPC patients treated with ECF were identified, of which 8 had liver metastases. The median age was 56 (range: 42-76) and all had multiple poor prognostic features. A median of 6 cycles of ECF were administered (range: 1-10) and toxicities were similar to previous reports. Of the 8 patients with liver metastases, 5 had partial remission. CONCLUSIONS: ECF was highly active in this small selected group of younger men with liver metastases from CRPC and multiple poor prognostic features. Despite important limitations, this is the third report of high objective response rates with ECF in CRPC. Objective response rates are low with current monotherapies. A higher probability of ORR is preferred for critical organ disease, therefore the anti-tumour activity should encourage testing of ECF in comparison to the most active current therapies.