NCCN Clinical Practice Guidelines in Oncology: 2019 Updates
In 1996, the National Comprehensive Cancer Network® (NCCN®) published its first set of Clinical Practice Guidelines in Oncology (NCCN Guidelines®), covering eight tumor types. NCCN Guidelines are now published for more than 70 tumor types and topics. Some of the key updates for 2019 were presented at the NCCN’s 2019 Annual Conference and are summarized here. Speakers at the meeting also addressed key changes in the 8th edition of the American Joint Committee on Cancer (AJCC) staging systems for breast, testicular, and head and neck cancers.
Melinda L. Telli, MD
“The panel continues to specifically endorse the 21-gene recurrence score in node-negative disease, based on the phase III TAILORx trial, and we have updated recommendations for the ‘gray area’ of patients with recurrence scores of 26 to 30.”
—Melinda L. Telli, MD
Updates in breast cancer were presented by three experts: John H. Ward MD, the Margaret A. Amundsen Endowed Professor of Medicine at the University of Utah School of Medicine and an oncologist at the Huntsman Cancer Institute, Salt Lake City, who discussed molecular testing; William J. Gradishar MD, FASCO, the Betsy Bramsen Professor of Breast Oncology, Professor of Medicine, and Chief of Hematology and Medical Oncology at the Feinberg School of Medicine at Northwestern University, Chicago, who updated attendees on the management of hormone receptor–positive metastatic disease; and Melinda L. Telli, MD, Associate Professor of Medicine (Oncology) at Stanford University Medical Center, Stanford, California, who described new recommendations in hormone receptor–positive early-stage disease.
The following are updates to the NCCN Guidelines for Breast Cancer:
- The use of the 21-gene assay recurrence score has been refined for assigning node-negative patients to endocrine therapy alone or with chemotherapy, based on the 2018 results of the TAILORx trial. Other gene-expression profiles, which are prognostic but not predictive, can be used to help assess risk in patients with one to three positive lymph nodes.
- The algorithm for treating the axillary lymph nodes has been refined. For patients with operable disease who will undergo surgery as primary treatment, the recommendation is to stratify patients according to the presence or absence of clinically positive lymph nodes. A patient with biospy-confirmed positive axilla planned for initial breast conservation surgery can proceed with axillary lymph node dissection or, if she meets all the ACOSOG Z0011 trial criteria and also has low tumor burden (image detected only, limited to 1 or 2 nodes), sentinel lymph node biopsy can be considered.
- Ovarian suppression in combination with tamoxifen or an aromatase inhibitor has been validated as an optimal approach in high-risk premenopausal women with hormone receptor–positive breast cancer, based on an updated analysis of the pivotal SOFT and TEXT trials.
- In the metastatic setting, the guidelines further reinforce the benefit of the CDK4/6 inhibitors, extending the “preferred” recommendation to all the available agents in metastatic disease.
- Options in metastatic triple-negative breast cancer now include an immunotherapeutic for the first time, atezolizumab with nab-paclitaxel, for patients expressing programmed cell death ligand 1 (PD-L1).
- In patients with HER2-negative tumors, BRCA1/2-mutated tumors, a new PARP inhibitor, talazoparib, has been added.
Eric Jonasch, MD
“Classification of renal cell carcinoma is becoming increasingly important. It is no longer just an academic curiosity.”
—Eric Jonasch, MD
Eric Jonasch, MD, Professor in the Department of Genitourinary Oncology at The University of Texas MD Anderson Cancer Center, Houston, and Vice-Chair of the NCCN Kidney Cancer Panel, discussed kidney cancer, for which the main updates include:
- In a major shift in risk categorization that is used for designating “preferred” and “other recommended” first-line treatments, “good risk” is now its own risk category, and “intermediate risk” and “poor risk” are combined in one category. This has implications for treatment.
- Ipilimumab/nivolumab along with cabozantinib are appropriate for treatment of patients with intermediate- and poor-risk disease.
- Pembrolizumab/axitinib and avelumab/axitinib may become options for all risk groups. Fewer patients achieve complete responses with these regimens, as compared to ipilimumab/nivolumab.
- Good-risk patients can consider sunitinib and pazopanib until combinations of immunotherapy agents and tyrosine kinase inhibitors are approved.
Matthew A. Gubens, MD, MS
Immunotherapy in Metastatic NSCLC
“PD-L1 testing is essential for selecting the best first-line options for our patients with metastatic lung cancer.”
—Matthew A. Gubens, MD, MS
Updates in metastatic non–small cell lung cancer (NSCLC), especially with regard to immunotherapy, were presented by Matthew A. Gubens, MD, MS, Associate Professor of Medicine (Hematology/Oncology) at UCSF and a treating physician at the UCSF Helen Diller Family Comprehensive Cancer Center, along with Marianne Davies, DNP, RN, CNS, ACNP-BC, AOCNP, Assistant Professor of Nursing and Clinical Instructor at Yale University and Yale Cancer Center/Smilow Cancer Hospital, New Haven, Connecticut. Dr. Davies discussed toxicities related to immunotherapy in NSCLC.
- The guidelines for immunotherapy in metastatic NSCLC reflect the importance of assessing levels of expression of PD-L1 based on 2018 data from KEYNOTE-407, KEYNOTE-189, and IMpower-150.
- For patients lacking a driver mutation (eg, EGFR, ALK) and with ≥ 50% expression of PD-L1, treatment with single-agent pembrolizumab is preferred. However, combination immunotherapy/chemotherapy regimens are also recommended. Preferred interventions are based on efficacy, safety, and evidence.
- For patients with PD-L1 < 50% and no driver mutations, it is important to distinguish nonsquamous from squamous cell tumors.
- For patients with nonsquamous disease, pembrolizumab plus carboplatin (or cisplatin) and pemetrexed is preferred. A four-drug regimen of carboplatin, paclitaxel, bevacizumab, and atezolizumab is also reasonable, especially for patients ineligible for pemetrexed therapy.
- For patients with squamous cell disease, carboplatin plus paclitaxel (or nab-paclitaxel) with pembrolizumab is preferred.
- Clinicians treating NSCLC with immunotherapy are encouraged to consult with other specialists in the management of toxicities.
James L. Mohler, MD
“Use of oral drugs [that delay time to metastasis] will add another $400,000 per year to the cost of treatment. If you have nonmetastatic castration-resistant prostate cancer, you can expect to live at least 2 years from the time your disease becomes metastatic. The costs of treatment are increased to $1 million. We need to consider costs and financial distress. The financial burden of prostate cancer has a greater impact on survivors than any of the other seven common cancers.”
—James L. Mohler, MD
Updates to the NCCN Guidelines for Prostate Cancer include further refinements in taking a family history, new recommendations for germline and somatic testing, use of androgen receptor blockers upfront in men at high risk for the
Emmanuel S. Antonarakis, MD
development of metastases, continued advice regarding intermittent vs continuous androgen-deprivation therapy, and consideration of whether to treat the primary tumor in men diagnosed with de novo metastatic prostate cancer. These key updates were presented by James L. Mohler, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, and Emmanuel S. Antonarakis, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
- Patients with regional or metastatic prostate cancer and those with localized prostate cancer and a suspicious family history should undergo germline testing for the following genes associated with an increased incidence and/or aggressiveness of prostate cancer: MLH1, MSH2, MSH6, PMS2 (for Lynch syndrome), and the homology-directed repair genes BRCA1, BRCA2, ATM, PALB2, and CHEK2. Next-generation sequencing can be used.
- The new guidelines distinguish between intraductal and ductal carcinomas. A higher incidence of germline mutations is found in intraductal cancers, which can have treatment implications. Patients with intraductal prostate cancer should undergo germline testing as previously noted.
- Patients with intermediate-risk disease are now categorized as favorable vs unfavorable risk. Active surveillance may be appropriate for some favorable intermediate-risk patients.
- Intermittent androgen deprivation is considered as safe as continuous androgen-deprivation therapy for men with nonmetastatic prostate cancer. Intermittent androgen therapy should be considered in men with metastatic disease.
- Treatment of the primary tumor is controversial in men with low-volume metastatic prostate cancer.
- Second-generation androgen receptor blockers are recommended in addition to androgen-deprivation therapy for patients with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less.
Thomas W. Flaig, MD
Muscle-Invasive Bladder Cancer
“There has been no major change in the incidence of bladder cancer in the United States for 40 years, and for 30 years there has been almost no therapy in development for localized and advanced disease. But in the past few years, five immune checkpoint inhibitors have been approved for the treatment of bladder cancer.”
—Thomas W. Flaig, MD
Updates to the guidelines for muscle-invasive bladder cancer were presented by Thomas W. Flaig, MD, Professor of Medicine and Associate Dean, University of Colorado Cancer Center, Aurora. “We now have a lot more latitude in treating patients and we have support to pursue more aggressive therapy,” Dr. Flaig said. In the updated version:
- Staging changes have been integrated that reflect a new understanding of the natural history of the disease and will affect how patients are treated.
- The guidelines distinguish between patients with stage II disease who are -candidates for cystectomy and those requiring a noncystectomy approach.
- Five anti–programmed cell death protein 1 (anti–PD-1) or anti–PD-L1 checkpoint inhibitors are now approved for the treatment of bladder cancer: pembrolizumab nivolumab, atezolizumab, durvalumab, and avelumab.
- The U.S. Food and Drug Administration (FDA) has limited the use of checkpoint inhibitors as monotherapy in the first-line treatment of metastatic and advanced disease with low expression of PD-L1, which has led to new treatment considerations for cisplatin-ineligible patients. Patients who meet these criteria should receive gemcitabine in combination with carboplatin preferentially over a checkpoint inhibitor.
- Regardless of PD-L1 expression, patients who are not eligible for any platinum-containing chemotherapy can be treated in the first line with atezolizumab or pembrolizumab. Other options are gemcitabine or gemcitabine plus paclitaxel. Ifosfamide, doxorubicin, and gemcitabine may be useful for patients with good kidney function and a good performance status.
- Postplatinum pembrolizumab is a category 1 recommendation. The four other approved checkpoint inhibitors are alternative options.
- Post–checkpoint inhibitor, cisplatin-ineligible patients should preferentially receive gemcitabine/carboplatin. Platinum-eligible chemotherapy-naive patients can preferentially receive gemcitabine/cisplatin or DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) with growth factor support.
- Most experts acknowledge that PD-L1 is a suboptimal biomarker for response to immune checkpoint inhibitor therapy. The tests are not standardized, and each pharmaceutical company has its own platform. The development of better biomarkers will be key to patient selection for therapy.
Wells A. Messersmith, MD, FACP
Metastatic Colorectal Cancer
“The biggest updates are the additional options for BRAF-mutated cancers, tissue-agnostic approval for the NTRK inhibitor larotrectinib, and some additional language regarding Lynch syndrome and testing, both in terms of the expression of the markers and the fact that a BRAF mutation doesn’t rule out Lynch syndrome.”
—Wells A. Messersmith, MD, FACP
A number of important changes were made to the NCCN Guidelines for Colon Cancer and the NCCN Guidelines for Rectal Cancer, as presented by Wells A. Messersmith, MD, FACP, of the University of Colorado School of Medicine, Denver:
- In a major update, the panel incorporated new options for combination regimens in the treatment of BRAF V600E–mutated colorectal cancer. As second-line therapy options, the guidelines now include dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor), plus cetuximab or panitumumab (EGFR antibody); or encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) plus cetuximab or -panitumumab.
- Larotrectinib was added as a subsequent treatment option in patients with metastatic colorectal cancer who have neurotrophic receptor tyrosine
- kinase (NTRK) gene fusions. The FDA also granted tissue-agnostic approval for use of the drug in patients with NTRK gene fusions.
- The updated guidelines added a cautionary note that although microsatellite instability (MSI)-high status or mismatch repair deficiency (dMMR) associated with the BRAF V600E mutation is usually due to epigenetic mechanisms and is not inherited, it does not rule out Lynch syndrome. The guidelines now recommend germline testing if there is a strong family history.
- Combination immunotherapy options for dMMR/MSI-high advanced colorectal cancer are now included. In the first-line setting, nivolumab or pembrolizumab, or a combination of nivolumab and ipilimumab, are listed as category 2B recommendations for patients with dMMR/MSI-high disease who are not appropriate for treatment with cytotoxic combinations.
- An additional treatment option of modified FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) plus panitumumab or cetuximab was added for patients with unresectable metastatic colorectal cancer with synchronous liver and/or lung metastases alone, KRAS/NRAS/BRAF wild-type, and left-sided tumors.
Margaret A. Tempero, MD, FASCO
“How will you find those patients who are eligible for targeted drugs if you don’t profile them? I think we are going to have more drugs that are ‘agnostic’ for tumor types (such as larotrectinib and pembrolizumab), so this will become more important.”
—Margaret A. Tempero, MD, FASCO
For the first time in decades, advances in diagnostics and adjuvant therapies appear to be improving outcomes in pancreatic cancer. These findings are reflected in additions to the NCCN Guidelines for Pancreatic Cancer (v1.2019), according to Margaret A. Tempero, MD, FASCO, who has chaired the NCCN Pancreatic Adenocarcinoma Panel for 20 years. Dr. Tempero is Professor of Medicine and Director of the University of California, San Francisco, (UCSF) Pancreas Center at the UCSF Helen Diller Family Comprehensive Cancer Center. For diagnosing and treating pancreatic cancer, the NCCN newly recommended in v1.2019:
- Consider germline testing for any patient with pancreatic cancer, based on the fact that a surprising number of germline mutations occur in patients without a family history of the disease, who would not meet current criteria for screening.
- Consider molecular analysis of tumors in persons with metastatic disease, based on an increasing number of actionable mutations.
- Consider adjuvant therapy with modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) for patients who can tolerate it, based on the phase III Unicancer GI PRODIGE 24/CCTG PA.6 trial, in which adjuvant modified FOLFIRINOX resulted in the longest overall survival yet reported for patients with pancreatic cancer following resection: 54.4 months, compared to 35.0 months with gemcitabine (hazard ratio [HR] = 0.64; P = .003).
Suzanne George, MD
“The importance of understanding specific sarcoma histologies, as well as the impact of systemic therapy choices on specific sarcoma subtypes, continues to evolve and mature in the sarcoma world.”
—Suzanne George, MD
Suzanne George, MD, of Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston, discussed updates in the guidelines for soft-tissue sarcomas, including the following changes:
- Preliminary results from the phase III ANNOUNCE trial led to the removal of olaratumab (as systemic therapy in combination with doxorubicin) from the NCCN Guidelines. Doxorubicin still stands on its own as a single agent, as ongoing trials with olaratumab in soft-tissue sarcoma continue.
- Based on positive findings for regorafenib in various soft-tissue sarcoma subtypes (eg, leiomyosarcoma, synovial sarcoma), regorafenib is now included as a systemic therapy option for non–gastrointestinal stromal tumor (GIST) sarcomas (though not in the first line).
- Pazopanib was added to the NCCN Guidelines as a histology-specific option for alveolar soft-part sarcoma. Pembrolizumab was also approved as a histology-specific category 2B recommendation for this subtype.
- Based on dramatic responses in a study of larotrectinib in NTRK fusion–positive cancers (not just sarcomas), the drug was added to the NCCN Guidelines for sarcomas with NTRK fusions.
Neil P. Shah, MD, PhD
Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
“Based upon data presented a couple of years ago, we decided to modify the guidelines to incorporate tyrosine kinase inhibitor discontinuation as a reasonable option in select patients. These guidelines have only been around for about 2.5 years, so in the past year nothing has really changed. To this day, some clinicians are not aware that stopping therapy with these agents is an option.”
—Neil P. Shah, MD, PhD
Neil P. Shah, MD, PhD, of the UCSF Helen Diller Family Comprehensive Cancer Center, discussed the NCCN Guidelines for Chronic Myeloid Leukemia (CML), noting that although no major updates were introduced this year in regard to discontinuing tyrosine kinase inhibitor therapy, there is a need to reinforce the criteria for tyrosine kinase inhibitor discontinuation outlined in the current guidelines. He said that when combined with careful molecular monitoring, the guidelines reinforce the safety of tyrosine kinase inhibitor discontinuation in appropriate and consenting patients with chronic-phase CML who have achieved and maintained a deep molecular response. Specifically, Dr. Shah said:
- Achievement and maintenance of a deep molecular response characterized by ≥ 4-log reduction in BCR-ABL1 transcripts (MR4; BCR-ABL1 ≤ 0.01%) that is sustained for at least 2 years is required before considering tyrosine kinase inhibitor discontinuation outside the context of a clinical trial. The loss of a major molecular response (MR3; BCR-ABL1 ≤ 0.1%) should trigger immediate resumption of tyrosine kinase inhibitor therapy, with monthly monitoring, until a major molecular response is regained.
- Patients who wish to stop tyrosine kinase inhibitor therapy should consult with a CML specialty center regarding risks and benefits, which include tyrosine kinase inhibitor withdrawal syndrome.
- In patients with CML who relapse after discontinuing tyrosine kinase inhibitor therapy, a second tyrosine kinase inhibitor discontinuation can be successful among those who regained a sustained deep molecular response following tyrosine kinase inhibitor rechallenge, but data regarding the success rate are limited.
- Second-generation tyrosine kinase -inhibitors have demonstrated improved rates of deep molecular response, making treatment discontinuation possible for more patients.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
- Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
- Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
- Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
- Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
8th Edition of the AJCC Cancer Staging Manual
A noteworthy session at the NCCN Annual Conference was devoted to a discussion of changes in the 8th edition of the AJCC Cancer Staging Manual for breast, testicular, and head and neck cancers. Experts in each cancer reviewed the respective changes and weighed in on whether they viewed the changes as clinically helpful. The testicular cancer changes came under fire for being more helpful to pathologists than to clinicians.
Aysegul A. Sahin, MD
Breast Cancer Staging
“A major improvement in the AJCC staging system is clarification of the pathologic evaluation of both T stage and N stage using a lot of illustrations and descriptive explanations.”
—Aysegul A. Sahin, MD
The changes in the management of breast cancer included in the 8th edition of the AJCC Cancer Staging Manual were discussed by Aysegul A. Sahin, MD, Director of Educational Operations and Professor in the Department of Pathology at The University of Texas MD Anderson Cancer Center, Houston.
The new staging system incorporates biologic factors into staging, in addition to the classic factors such as TNM status. Stage, grade, estrogen receptor status, and HER2 status are now included.
- Molecular subtyping is also suggested for invasive breast cancer. Multigene panels are included as stage modifiers for hormone receptor–positive, HER2-negative, lymph node–negative breast cancer.
- The new staging system includes additional clarification of pT and pN status.
- Lobular carcinoma in situ has been dropped from the staging system.
Timothy D. Gilligan, MD, FASCO
Testicular Cancer Staging
“It is questionable whether we should alter our management of these patients based on these histopathologic findings. We need better studies to answer these and other questions.”
—Timothy D. Gilligan, MD, FASCO
In general, the new staging system for patients with testicular cancer raises more questions than it answered, according to Timothy D. Gilligan, MD, FASCO, Vice-Chair for Education and Associate Professor of Medicine at the Cleveland Clinic Taussig Cancer Institute, who took issue with a number of the changes made since the 7th edition. He believes that these changes are more important for pathologists than clinicians and that they will have minimal impact on the clinical management of patients with testicular cancer.
- The pT1 designation for seminoma of the testes is now divided according to size: pT1a tumors are < 3 cm; pT1b are ≥ 3 cm. Dr. Gilligan thinks this is an appropriate distinction, as larger tumors are associated with a higher risk of relapse in patients with clinical stage I disease.
- Epididymal invasion and hilar tissue invasion have been upstaged from pT1 to pT2. Dr. Gilligan questioned the appropriateness of this change, noting that epididymal invasion is rare and has not been associated with a higher risk of relapse in large studies of patients with clinical stage I disease. The rationale for the change was not based on risk of relapse but rather on the argument that cancer can’t invade the epididymis without first invading the hilar soft tissue. Invasion of the hilar tissue is a better marker of more aggressive cancer, but again, there are no strong data linking invasion of hilar soft tissue with risk of relapse.
- Noncontinuous invasion of the spermatic cord is no longer categorized as T3 but is now considered a metastasis. He doubted that clinicians will treat this as metastatic cancer in the absence of data showing that such invasion is associated with higher relapse rates or worse outcomes.
- Dr. Gilligan observed that a recent study found “alarming” discrepancies in the way different pathologists stage testicular cancer and noted that the changes in testicular cancer staging appear to be aimed primarily at achieving more standardized pathologic evaluation.
Jimmy J. Caudell, MD, PhD
Head and Neck Cancer Staging
“The 7th edition of AJCC worked well for human papillomavirus (HPV)-negative oropharyngeal cancers but lost prognostic significance for HPV-positive cancers. We needed to improve staging for HPV-positive patients, who comprise the majority of patients with head and neck cancer.”
—Jimmy J. Caudell, MD, PhD
Changes in the staging system are significant and are considered an advance for HPV-positive head and neck cancer, but there is still room for improvement for staging of HPV-negative cancers, according to Jimmy J. Caudell, MD, PhD, Associate Member in the Head and Neck Program at Moffitt Cancer Center, Tampa, Florida.
For HPV-positive tumors:
- The new system collapses categories T4a and T4b into one category—T4.
- N1, N2a, and N2b are now all considered N1 in the 8th edition of the AJCC Cancer Staging Manual.
- Current treatment guidelines have not changed, and data from studies on de-escalation strategies are awaited.
For HPV-negative tumors:
- The T category is unchanged. T4a and T4b are retained.
- New clinical N3a and N3b designations are based on extracapsular extension and modifications to pathological N category based on extracapsular extension.
- Changes were based primarily on patients with cancers of the oral cavity.
- The impact of the current treatment paradigms is unclear.
- The role of intensification strategies remains to be established.
Anthony J. Olszanski, MD, RPh
Cutaneous Melanoma Staging
“Patients with stage III melanoma are at high risk for disease recurrence, but adjuvant therapy—including targeted therapy and immunotherapy—may prevent or delay relapse.”
—Anthony J. Olszanski, MD, RPh
Anthony J. Olszanski, MD, RPh, of Fox Chase Cancer Center, Philadelphia, discussed the most significant updates to the treatment of cutaneous melanoma:
- In the updated 8th edition of the AJCC staging criteria, M1c is now described as metastasis to additional organs but no longer includes central nervous system (CNS) metastasis; a new M1d designation includes distant CNS metastasis, with or without other distant sites of disease.
- The new staging increases the proportion of patients diagnosed with stage III disease, to > 20%.
- A new category in stage III disease—stage IIID—has been added.
- Based on relapse-free survival data in the adjuvant setting, PD-1 inhibitors nivolumab and pembrolizumab are now incorporated into the adjuvant treatment guidelines for stage III cutaneous melanoma.
- For patients with BRAF V600E/K disease, targeted therapy using dabrafenib and trametinib is also reflected in the guidelines as an appropriate treatment option.
- Results of the MSLT-II trial showed that ultrasound-guided follow-up can be done in lieu of complete lymph node dissection in patients with sentinel node–positive disease without adversely affecting survival. ■
MORE FROM NCCN
For more from the 2019 NCCN Annual Conference, see interviews with William J. Gradishar, MD, FASCO; Matthew A. Gubens, MD, MS; Eric Jonasch, MD; Melinda L. Telli, MD; Neil P. Shah, MD, PhD; Margaret A. Tempero, MD, FASCO; Wells A. Messersmith, MD, FACP, and others on The ASCO Post Newsreels at www.ascopost.com/videos.
DISCLOSURE: Dr. Telli has served as a scientific advisor for Aduro, Celgene Corporation, Genentech, Immunomedics, Merck, and Pfizer. Dr. Gradishar has served as a scientific advisor for AstraZeneca, MacroGenics, Roche, and Seattle Genetics. Dr. Gubens has consulted for AstraZeneca, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Genentech, Heron, Roche, and Takeda and has received grants or research support from Celgene, Merck, Novartis, and OncoMed. Dr. Davies has served on product/speakers bureaus for AstraZeneca, Bristol-Myers Squibb, Genentech, and Merck. Dr. Flaig has received grants or research support from Agensys, Aragon, Astellas Pharma US, AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, Dendreon Corporation, Eli Lilly, Exelixis, Genentech, Hoffmann La Roche, Janssen Pharmaceuticals, Merck, Pfizer/Hospira, Seattle Genetics, Sotio, and Tokai and has an equity interest or stock in Aurora Oncology. Dr. George has consulted/advised for or received research support from Bayer HealthCare, Blueprint Medicines, Deciphera Pharmaceuticals, Eli Lilly, and Pfizer. Dr. Messersmith has consulted for Agendia BV, Amgen, Genomic Health, Halozyme, Mylan, Partners Healthcare, Pfizer, Samsung Bioepis, and Spectrum Pharmaceuticals. Dr. Shah has received grants or research support from Bristol-Myers Squibb. Dr. Olszanski has received honoraria from Alkermes, Array, EMD Serono, Iovance, Merck, Novartis, and Pfizer. Drs. Mohler, Sahin, Gilligan, Caudell, Tempero, Ward, and Jonasch reported no conflicts of interest.