It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.
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Heather H. Cheng, Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small and Celestia S. Higano
Linda Overholser and Carlin Callaway
Most cancer survivors will follow-up with primary care at some point in the cancer continuum, but coordination between the oncology and primary care teams remains challenging. According to Drs. Linda Overholser and Carlin Callaway, who discussed the importance of care coordination to improve outcomes in cancer survivors at the NCCN 2019 Annual Conference, effective communication is needed between specialists and primary care providers and, when established, has been shown to improve treatment outcomes. Use of survivorship care plans, as well as adherence to the NCCN Guidelines for Survivorship, can further standardize the provision of quality oncology care.
U-Syn Ha, Jin Bong Choi, Jung Im Shim, Minjoo Kang, Eunjung Park, Shinhee Kang, Jooyeon Park, Jangmi Yang, Insun Choi, Jeonghoon Ahn, Cheol Kwak, Chang Wook Jeong, Choung Soo Kim, Seok-Soo Byun, Seong Il Seo, Hyun Moo Lee, Seung-Ju Lee, Seung Hwan Lee, Byung Ha Chung and Ji Youl Lee
Background: We conducted a comparative survival analysis between primary androgen deprivation therapy (PADT) and radical prostatectomy (RP) based on nationwide Korean population data that included all patients with prostate cancer. Materials and Methods: This study enrolled 4,538 patients with prostate cancer from the National Health Insurance Service (NHIS) database linked with Korean Central Cancer Registry data who were treated with PADT or RP between January 1, 2007, and December 31, 2014. Kaplan-Meier and multivariate survival analyses stratified by stage (localized and locally advanced) and age (<75 and ≥75 years) were performed using a Cox proportional hazards model to evaluate treatment effects. Results: Among 18,403 patients from the NHIS database diagnosed with prostate cancer during the study period, 4,538 satisfied inclusion criteria and were included in the analyses. Of these, 3,136 and 1,402 patients underwent RP or received PADT, respectively. Risk of death was significantly increased for patients who received PADT compared with those who underwent RP in the propensity score–matched cohort. In subgroup analyses stratified by stage and age, in every subgroup, patients who received PADT had a significantly increased risk of death compared with those who underwent RP. In particular, a much greater risk was observed for patients with locally advanced prostate cancer. Conclusions: Based on a nationwide survival analysis of nonmetastatic prostate cancer, this study provides valuable clinical implications that favor RP over PDAT for treatment of Asian populations. However, the possibility that survival differences have been overestimated due to not accounting for potential confounding characteristics must be considered.
A Focus on CAR T-Cell Therapy
The use of innovative treatments such as chimeric antigen receptor (CAR) T-cell therapy is rapidly expanding. The challenges of receiving and delivering this novel therapy were discussed at the NCCN 2019 Annual Conference’s keynote session. In a separate roundtable discussion, additional stakeholders discussed how payers and providers are grappling with the cost of incorporating CAR T-cell therapy into practices.
Dwight H. Owen, Bhavana Konda, Jennifer Sipos, Tom Liu, Amy Webb, Matthew D. Ringel, Cynthia D. Timmers and Manisha H. Shah
BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine–refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V–activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.
ClinicalTrials.gov identifier: NCT01723202
Thomas Kaley and Louis B. Nabors
Meningiomas represent a full spectrum of tumors that are the most common type of brain tumor in adults. Although most are benign, recent research has shown that the recurrence rate is high, especially for WHO grades 2 and 3, and overall survival is poor for these grades. Treatment is evolving, and recently sunitinib and bevacizumab have shown promise compared with historical treatments. However, more research is needed to identify better treatments for meningiomas. Treatment of brain metastases is another evolving field. Studies suggest that stereotactic radiosurgery is preferable to whole-brain radiation therapy and that immune checkpoint inhibitors and therapies targeted to the T790M mutation and ALK can improve outcomes in patients with non–small cell lung cancer and brain metastases.
Judith A. Paice
Advances in cancer treatment have led to a growing number of survivors. At least 40% of those survivors live with chronic pain and need pain control medication. This coincides with an epidemic of opioid misuse and overdose deaths, resulting in restrictive practices that can impact patients who experience severe pain. Oncologists and other healthcare professionals who treat patients with cancer need to balance considerations of opioid misuse with effective pain control and become better educated about risk factors and management of opioids in cancer survivors.
Anthony J. Olszanski
According to Dr. Anthony J. Olszanski, the most significant updates to the treatment of cutaneous melanoma include the recently published results of MSLT-II, which demonstrated that ultrasound-guided follow-up can be performed rather than a complete lymph node dissection, improving morbidity in patients with sentinel node metastases while not adversely affecting survival. In the adjuvant setting, the PD-1 inhibitors nivolumab and pembrolizumab are now FDA-approved, in addition to dabrafenib and trametinib, for patients with BRAF mutations.
Featured Updates to the NCCN Guidelines
Patrick A. Brown, Matthew Wieduwilt, Aaron Logan, Daniel J. DeAngelo, Eunice S. Wang, Amir Fathi, Ryan D. Cassaday, Mark Litzow, Anjali Advani, Patricia Aoun, Bhavana Bhatnagar, Michael W. Boyer, Teresa Bryan, Patrick W. Burke, Peter F. Coccia, Steven E. Coutre, Nitin Jain, Suzanne Kirby, Arthur Liu, Stephanie Massaro, Ryan J. Mattison, Olalekan Oluwole, Nikolaos Papadantonakis, Jae Park, Jeffrey E. Rubnitz, Geoffrey L. Uy, Kristina M. Gregory, Ndiya Ogba and Bijal Shah
Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.