PracticeUpdate: Oncology - Winter 2018

VOL. 2 • NO. 3 • WINTER 2018

OUR EXPERTS. YOUR PRACTICE.

ISSN 2207-869X

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

American Society of Clinical Oncology 2018 Annual Meeting European Hematology Association 2018 Congress Three-Month Posttreatment Prostate- Specific Antigen Level as a Biomarker of Treatment Response in Patients With Intermediate-Risk or High-Risk Prostate Cancer Treated With Androgen Deprivation Therapy and Radiotherapy

JOURNAL SCANS Progression-Free Survival at 24 Months (PFS24) and Subsequent Outcome for Patients With Diffuse Large B-Cell Lymphoma (DLBCL) Enrolled on Randomized Clinical Trial

Association of Circulating Tumor Cell Status With Benefit of Radiotherapy and Survival in Early-Stage Breast Cancer

BREAK THE CYCLE With the first PBS listed CDK4/6 inhibitor - from 1 st July 1,2

As initial endocrine treatment for HR+/HER2– locally advanced (inoperable) or metastatic breast cancer, in combination with letrozole or anastrozole for men and postmenopausal women. 1,2

PBS Information: Authority Required. Refer to the PBS Schedule for full Authority information.

PLEASE REVIEW PRODUCT INFORMATION BEFORE PRESCRIBING. APPROVED PRODUCT INFORMATION IS AVAILABLE ONLINE AT WWW.NOVARTIS.COM.AU/PRODUCTS/ HEALTHCARE-PROFESSIONALS.SHTML OR WWW.EBS.TGA.GOV.AU Kisqali ® (ribociclib): Indication: In combination with an aromatase inhibitor, for the treatment of men and postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, as an initial endocrine therapy. Contraindications: QTcF>450ms; hypersensitivity to active substance, ingredients, soy products. Precautions: ECG, CBC, serum electrolytes, LFTs, and pregnancy status must be assessed prior to initiation of treatment. QT interval prolongation, hepatobiliary toxicity, neutropenia (including febrile). Monitoring during treatment – see full PI. Pregnancy (Category D), effective contraception, lactation, fertility. Interactions: Strong CYP3A inhibitors or inducers. Caution with narrow therapeutic index CYP3A substrates. Monitor for ADRs. Avoid co-administration with drugs that have a potential to prolong the QT interval. Avoid pomegranate, grapefruit. Adverse effects: Very common (≥10%): UTI, neutropenia, leukopenia, anaemia, lymphopenia, decreased

TREAT early

First line treatment for HR+, HER2- ABC in men and postmenopausal women in combination with an aromatase inhibitor 1

EXTEND control

NOW PBS LISTED!

Over 2-year median PFS in combination with letrozole 3,4 With 54.7% of patients progression free at 2-years 3 out of 4 patients experienced tumour reduction as early as week 8 in combination with letrozole 5† † subgroup analysis of patients with measurable disease at baseline

REDUCE risk

43.2% reduced risk of progression or death in combination with letrozole 1 Vs. placebo + letrozole at 2-years (HR=0.568, 95% CI: 0.457—0.704, P<0.0001) 1

appetite, headache, insomnia, dyspnoea, back pain, nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain, alopecia, rash, pruritus, fatigue, peripheral oedema, asthenia, pyrexia, abnormal LFTs, leukocyte count decreased, neutrophil count decreased, haemoglobin decreased, lymphocyte count decreased, platelet count decreased, ALT increased, AST increased, creatinine increased, phosphorous decreased, potassium decreased. Common (1-10%): thrombocytopenia, febrile neutropenia, lacrimation increased, dry eye, hypocalcaemia, hypokalaemia, hypophosphataemia, syncope, epistaxis, dysgeusia, dyspepsia, hepatotoxicity, erythema, peripheral oedema, weight decreased, ECG QT prolonged, bilirubin increased. Dosage: Adults - Kisqali 600 mg taken orally, once daily for 21 consecutive days followed by 7 days off treatment, in repeating cycles of 28 days. Caution in severe renal impairment and/or moderate or severe hepatic impairment. Kisqali may require dose interruption, reduction, or discontinuation. Safety and efficacy not established in paediatrics, adolescents. Refer to full Kisqali PI and aromatase inhibitor PI. (kis120218m) ABBREVIATIONS: CDK, cyclin dependent kinase; HR+, hormone receptor positive; HER-, human epidermal growth factor receptor negative; ABC, advanced breast cancer; PFS, progression free survival; HR, hazard ratio; CI, confidence interval. REFERENCES: 1. Kisqali Product Information. 2. Pharmaceutical Benefits Scheme. Available at: www.pbs.gov.au. Accessed July 2018. 3. Hortobagyi GN et al. N Engl J Med. 2016;375(18):1738-1748. 4. Hortobagyi GN et al. Poster 1038: ASCO June 2-6, 2017; Chicago, IL. 5. Burris HA et al . Burris HA et al . Poster P4-22-16: SABCS Dec 6-10, 2016; San Antonio, TX.

Novartis Pharmaceuticals Australia Pty Limited ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555. ® Registered Trademark. Item No: AU-6242. Date of preparation July 2018. 3013RC.

PRACTICEUPDATE ONCOLOGY BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Lee Schwartzberg MD, FACP Executive Director, West Cancer Center; Professor of Medicine and Division Chief of Hematology/ Oncology, The University of Tennessee Health Science Center, Tennessee

PracticeUpdate® is a registered trademark of Elsevier Inc.

2018 Elsevier Inc. All rights reserved.

ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-Home Message designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Oncology provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Oncology are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by com- mercial sponsors or content contributors. DISCLAIMER PracticeUpdate Oncology has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The printing and distribution of this publication has been made possible through paid advertising. The editorial content herein is independently produced by Elsevier with no involvement by the advertiser. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. All content printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission from MEDLINE/ PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLM assumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: SEM of a breast cancer cell/gettyimages.com PracticeUpdate Oncology is published by Elsevier Australia ISSN 2207-869X (Print) ISSN 2207-8703 (Online)

Associate Editors

Isabel Cunningham MD Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons, New York Benjamin Anderson MD, FACS Professor of Surgery and Global Health-Medicine, University of Washington; Director, Breast Health Clinic, Seattle Cancer Care Alliance,

Axel Grothey MD Consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic; Professor of Oncology, Clinical and Translational Science, Mayo Graduate School, Rochester, Minnesota David Henry MD Clinical Professor of Medicine, Pennsylvania Hospital, Philadelphia, Pennsylvania Eric Jonasch MD Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine; Director, VHL Clinical Center, The University of Texas MD Anderson Cancer Center, Houston, Texas Jeffrey Kirshner MD, FACP Partner of Hematology Oncology Assoc of Central New York, East Syracuse; Director of Research, HOACNY Community Clinical Oncology Program, New York Howard Scher MD Chief, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan- Kettering Cancer Center, New York David Straus MD Attending Physician, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York Roger Stupp MD Professor of Neurological Surgery, Neurology, and Oncology, Northwestern University Feinberg School of Medicine; Co-Director, Northwestern Brain Tumor Institute; Associate Director for Strategic Initiatives, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois Sara M. Tolaney MD, MPH Medical Oncologist; Clinical Investigator, Breast Oncology Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts

Advisory Board

Seattle, Washington Roxana Dronca MD

Assistant Professor of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota

Wilfried Eberhardt MD Associate Director, Regional Outreach West German Cancer Centre University Hospital of University of Duisburg-Essen, Germany Wafiq S. El-Deiry MD, PhD, FACP Penn State Hershey Cancer Institute, Hershey, Pennsylvania; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Chair, Department of Internal Medicine; Mayo Clinic, Phoenix/Scottsdale, Arizona; Getz Family Professor of Cancer, Mayo Clinic School of Medicine, Phoenix/Scottsdale, Arizona Andre Goy MD Chairman and Director, John Theurer Cancer Center; Chief of Lymphoma, John Theurer Cancer Center, Hackensack University Medical Center, New Jersey Annette Hasenburg Prof. Dr. med. Director, Obstetrics and Gynecology, Mainz University Medical Center, Mainz, Germany

Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania Rafael Fonseca MD

Editorial Contributors

Neil Majithia MD Fellow in Hematology/Oncology, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota Jarushka Naidoo MD Assistant Professor of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, Maryland

Erin Schenk MD, PhD Hematology/Oncology Fellow,

Clinician-Investigator Training Program, Mayo School of Graduate Education

Jeffrey Wiisanen MD Hematology/Medical Oncology Fellow, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota

Moshe Ornstein MD Hematology/Oncology Fellow, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMON081801

CONTENTS 5

COVER 7

RESEARCH Editor’s picks 7 Adjuvant Chemotherapy Guided by a

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer Comment by Lee S Schwartzberg MD

21-Gene Expression Assay in Breast Cancer Comment by Lee S Schwartzberg MD

8 Ribociclib Plus Endocrine Therapy for

Premenopausal Women With HR+ Advanced Breast Cancer Comment by Reshma L Mahtani DO

EXPERT OPINIONS 20 10 Practice Changes That I Will Make After Attending ASCO 2018 By Jeffrey J Kirshner MD

9 Pembrolizumab vs Paclitaxel for Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer Comment by Axel Grothey MD 10 Clinical Consequences of Chemotherapy Dose Reduction in Obese Patients With Stage III Colon Cancer Comment by Axel Grothey MD 11 Progression-Free Survival at 24 Months and Subsequent Outcomes for Patients With DLBCL

22 Top 3 Advances in Radiation Oncology From ASCO 2018 Interview with Helen A Shih MD by Farzanna S Haffizulla MD

CONFERENCES 24 ASCO 2018 24 Lung Cancer Studies at ASCO 2018 Interview with Wilfried Eberhardt MD by Farzanna S Haffizulla MD 25 ASCO 2018: Best in Ovarian Cancer By Annette Hasenburg Prof. Dr. med. 26 Multiple Myeloma at ASCO 2018 Interview with Rafael D Fonseca MD by Farzanna S Haffizulla MD 26 ASCO 2018: Updates on PARP Inhibitors in Prostate Cancer Interview with Neeraj Agarwal MD by Sumanta Kumar Pal MD 27 Mirtazapine Prevents Delayed Nausea and Vomiting in Highly Emetogenic Chemotherapy By the PracticeUpdate Editorial Team 28 Patients With Advanced Cancer May Not Have to Accept Anorexia as Inevitable By the PracticeUpdate Editorial Team 29 Shorter Trastuzumab Treatment for HER2- Positive Breast Cancer Can Be as Effective,

30 EHA 2018 By the PracticeUpdate Editorial Team

11 Immune Recognition of Somatic Mutations Leading to Complete Durable Regression in Metastatic Breast Cancer 12 Sunitinib Alone or After Nephrectomy in Renal Cell Carcinoma Comment by Bradley G Somer MD 13 Circulating Tumor Cell Status Predicts Radiotherapy Benefit in Early Breast Cancer Comment by Lee S Schwartzberg MD 14 Three-Month Post-Treatment PSA Level as a Biomarker of Treatment Response in Patients With Intermediate- or High-Risk Prostate Cancer Treated With ADT and RT Comment by Brian E Lewis MD 15 Male Breast Cancer: An Updated SEER Data Analysis 16 Intravesical Instillation of Gemcitabine vs Saline After Resection of Suspected Low- Grade Non-Muscle Invasive Bladder Cancer Comment by Thomas J Guzzo MD 17 Risk Stratification of Smoldering Multiple Myeloma Incorporating Revised IMWG Diagnostic Criteria 18 Efficacy and Safety of ABP 980 Compared With Reference Trastuzumab in HER2+ Early Breast Cancer

30 Consider Obinutuzumab Plus Chlorambucil for First-Line Treatment for CLL 31 Neither Myeloablative nor Reduced-Intensity Conditioning Impact Overall Survival in T-Cell Lymphoma 32 Response Rates Improve Significantly With Three-Drug Combination for DLBCL 33 EUTOS Long-Term Survival Score Superior for Prognosis of Survival in CML 34 Rituximab Yields Durable Response in Adults With Persistent or Chronic Immune Thrombocytopenia

With Fewer Cardiac Side Effects By the PracticeUpdate Editorial Team

VOL. 2 • NO. 3 • 2018

When a geneticist dared to declare that mutations in one gene could be the source of hereditary breast cancer, it was an unprecedented idea.

UN PRECEDENTED Learn more at elsevier.com/empowering-knowledge

EDITOR’S PICKS 7

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer The New England Journal of Medicine Take-home message • In order to determine the value of chemotherapy in patients with midrange 21-gene breast cancer recurrence scores, this prospective trial evaluated 10,273 women with HR+/HER2−, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (HR for invasive disease recurrence, second primary cancer, or death [endocrine vs chemoendocrine therapy], 1.08; P = .26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine group and 84.3% in the chemoendocrine group) and freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). • The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P = .004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. Jeffrey Wiisanen MD

COMMENT By Lee S Schwartzberg MD, FACP T he TAILORx trial, presented at the ASCO plenary and simultaneously published in The New England Journal of Medicine , is a practice-chang- ing study. This NCI cooperative group trial result, a decade in the making, prospec- tively validated the ability of the Oncotype DX Recurrence Score (RS), based on a 21-gene genomic expression assay, to determine whether patients with HR+, HER2−, stage I–II early-stage breast can- cer (ESBC) benefited from chemotherapy in addition to endocrine adjuvant therapy. Over 6000 patients with an intermediate RS, defined as 11–25, were randomized to receive endocrine therapy alone or to also have chemotherapy of physician’s choice. The results conclusively showed

in distant disease-free recurrence. Was this a direct cytotoxic effect of the chemo- therapy or an indirect effect from causing menopause in this population? What about the patients who had an RS of 26 or greater and received chemo: was there a differential effect of the type of chemo- therapy regimen given? What is the slope of the curve for recurrence based on RS for these higher-risk patients, and do they all need chemotherapy, especially those with scores just above 25? This trial will continue to be a rich source of data on an ongoing basis as longer- term follow-up continues. For now, we have a convenient test that definitively helps oncologists and patients make an important decision in treatment for the most common women’s cancer.

no benefit with the addition of chemother- apy for patients with an RS in this range. Moreover, the risk of distant recurrence at 9 years was about only 5%. This builds on prior publication and now longer fol- low-up that showed patients with an RS of <10 have an excellent prognosis with endocrine therapy alone and would not benefit from chemotherapy. Therefore, the majority of women with ESBC can now be confidently assured of an excellent prognosis without adjuvant chemother- apy based on this genomic assay. As usual, the results of the TAILORx trial raise new questions. An exploratory anal- ysis suggested benefit for the subgroup of women younger than 50 years old and with an RS of 16–25, although this was a small percentage in terms of improvement

Abstract BACKGROUND The recurrence score based on the 21-gene breast can- cer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoen- docrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for inva- sive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive

disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemother- apy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-neg- ative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018 Jun 03;[EPub Ahead of Print], JA Sparano, RJ Gray, DF Makower, et al. www.practiceupdate.com/c/69142

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 8

Ribociclib Plus Endocrine Therapy for Premenopausal Women With HR+ Advanced Breast Cancer The Lancet Oncology Take-home message • This phase III trial evaluated the safety and efficacy of ribociclib or placebo plus endocrine therapy among premenopausal women with advanced, hormone recep- tor-positive breast cancer. Ribociclib was associated with a longer progression-free survival (23.8 vs 13.0 months). The safety profile was noted to be manageable in both groups. • The results suggest that ribociclib may be a new treatment option for premeno- pausal, HR-positive, HER2-negative, advanced breast cancer. Neil Majithia MD Abstract

COMMENT By Reshma L Mahtani DO T he incorporation of CDK4/6 inhibitors into the treatment of hormone receptor-positive, HER2-negative metastatic breast can- cer represents a paradigm shift for the management of these patients. There are currently three approved CDK4/6 inhibitors – palbociclib, ribociclib, and, most recently, abemaciclib. Although the PALOMA-3 and MONARCH 2 trials did include peri- and premenopausal women, the MONALEESA-7 trial is the only large randomized trial focusing specifically on this population. The trial results confirmed a significant benefit in progression-free survival and response rate with the addition of ribociclib to either aromatase inhibitors or tamoxifen. The efficacy benefits were maintained across prespecified subgroups, and the safety data were consistent with what has been previously reported with ribo- ciclib and endocrine therapies. These are important data in that they confirm the efficacy of the addition of CDK4/6 inhibitors to endocrine therapy in younger patients. These data also sup- port the use of tamoxifen as opposed to aromatase inhibitor therapy in these patients. Many patients report side effects to aromatase inhibitors; there- fore, tamoxifen is a reasonable option given the comparable efficacy noted in this trial.

BACKGROUND In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first- line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-nega- tive, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premen- opausal women with advanced, HR-positive breast cancer. METHODS This phase 3, randomised, dou- ble-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measura- ble disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-de- pendent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced dis- ease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week- off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anas- trozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investi- gators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. FINDINGS Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo

group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribo- ciclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respec- tively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontin- ued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast can- cer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient. INTERPRETATION Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-nega- tive, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. Ribociclib Plus Endocrine Therapy for Premenopausal Women With Hormone- Receptor-Positive, Advanced Breast Cancer (MONALEESA-7): A Randomised Phase 3 Trial. Lancet Oncol 2018 May 24;[EPub Ahead of Print], D Tripathy, SA Im, M Colleoni, et al. www.practiceupdate.com/c/68672

Dr. Mahtani is an Assistant Professor in the Division of Hematology/ Oncology at Sylvester Comprehensive Cancer Center, University of Miami Health System in Miami, Florida.

" These are important data in that they confirm the efficacy of the addition of CDK4/6 inhibitors to endocrine therapy in younger patients. "

PRACTICEUPDATE ONCOLOGY

EDITOR’S PICKS 9

Pembrolizumab vs Paclitaxel for Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer The Lancet

Take-home message • This phase III trial was designed to evaluate pembrolizumab vs paclitaxel for previously treated gastric or gastroesophageal junction cancer. Among patients with a PD-L1 combined positive score (CPS) of 1 or higher, there was no significant improvement with pembrolizumab in terms of progression-free or overall survival. The toxicity profile was favorable with pembrolizumab relative to paclitaxel. • Although pembrolizumab offered a better safety profile, it did not improve outcomes compared with paclitaxel. Neil Majithia MD COMMENT By Axel Grothey MD T he PD-1 antibodies pembroli- zumab and nivolumab both have recently obtained regulatory approval in various gastrointestinal malignancies, including PD-L1–posi- tive gastric cancer (pembrolizumab), hepatocellular cancer (nivolumab), and MSI-H/MMR-D colorectal cancer (both agents). All of these approvals were based on the results of single-arm tri- als without an active comparator. The KEYNOTE-061 study now compared pembrolizumab with paclitaxel as sec- ond-line therapy in PD-L1–positive, advanced gastroesophageal adenocar- cinoma. The study did not demonstrate an improved progression-free or overall survival for pembrolizumab and thus is negative. Having said that, the overall survival curve points to a plateau for pembrolizumab, which is about 10% higher than for paclitaxel. This could point to a subgroup of patients that enjoys a long-term benefit from the use of PD-1 antibodies in this disease, a subgroup that has yet to be further characterized.

one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. INTERPRETATION Pembrolizumab did not signifi- cantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Addi- tional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Pembrolizumab Versus Paclitaxel for Previously Treated, Advanced Gastric or Gastro-Oesoph- ageal Junction Cancer (KEYNOTE-061): A Randomised, Open-Label, Controlled, Phase 3 Trial. Lancet 2018 Jun 04;[EPub Ahead of Print], K Shitara, M Özgüroğlu, YJ Bang, et al. www.practiceupdate.com/c/69381 antibodies in this disease, a subgroup that has yet to be further characterized. " " This could point to a subgroup of patients that enjoys a long-term benefit from the use of PD-1

Abstract BACKGROUND Patients with advanced gastric or gastro-oesophageal junction cancer that pro- gresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oe- sophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. METHODS This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free sur- vival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). FINDINGS Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pem- brolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pem- brolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembroli- zumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03;

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 10

Clinical Consequences of Chemotherapy Dose Reduction in Obese Patients With Stage III Colon Cancer European Journal of Cancer

of using fully dosed chemotherapy for the adju- vant treatment in obese patients with colon cancer. Clinical Consequences of Chemotherapy Dose Reduction in Obese Patients With Stage III Colon Cancer: A Retrospective Analysis From the PETACC 3 Study. Eur J Cancer 2018 Aug 01;99(xx)49-57, G Stocker, UT Hacker, F Fiteni, et al. www.practiceupdate.com/c/69620 " …dose reductions should not be applied preemptively in overweight/obese patients unless other factors such as renal or hepatic function come into play. " COMMENT By Axel Grothey MD T he appropriate dosing of chemo- therapy in obese patients has long been a topic of discussion. Espe- cially in extremely obese patients, the calculated absolute dose of chemo- therapy can sometimes induce a “sticker-shock” andmight lead to a reflex dose reduction or a policy of capping BSA calculations at 2.0. In a palliative setting, potential mild under-dosing might not be as critical; but, in a curative, adjuvant setting, optimization of chemo- therapy dosing is a critical component of the treatment approach. In the current retrospective analysis of the adjuvant PETACC-3 trial in colon cancer, upfront dose reduction in obese patients was associated with decreased relapse-free survival in women, and, with a nonsig- nificant trend, also in men. These data add to the current body of evidence that dose reductions should not be applied preemptively in overweight/obese patients unless other factors such as renal or hepatic function come into play.

Take-home message • This retrospective study looked at the impact of dose reduction among obese patients treated with adjuvant chemotherapy for stage III colon cancer. Among patients with BMI ≥30 and a body surface area ≥2 m 2 , relapse-free survival was longer for those fully dosed vs dose-reduced (HR, 0.48), and there was a trend toward improved overall survival (HR, 0.53; P = .052). • The study authors concluded that it is appropriate to recommend fully dosed chemotherapy in the adjuvant setting for obese patients with colon cancer. Neil Majithia MD

Abstract BACKGROUND Dose reduction in obese cancer patients has been replaced by fully weight- based dosing recommendations. No data, however, are available on the effects of dose reduction in obese stage III colon cancer patients undergoing adjuvant chemotherapy. METHODS Survival outcomes and toxicity data of obese (body mass index [BMI] ≥30 kg/m 2 ), stage III colon cancer patients treated within the phase III PETACC 3 trial comparing leucov- orin, 5-FU (LV5FU2) with LV5FU2 plus irinotecan were analysed retrospectively according to chemotherapy dosing at first infusion (i.e. fully weight-based dosed – versus dose-reduced group). Multivariate analyses on relapse free survival (RFS) and overall survival (OS) were con- ducted to adjust for baseline prognostic factors using Cox regression model.

RESULTS 13.4% (280 of 2094 patients) had a BMI ≥30 kg/m 2 , and 5.3% had both a BMI ≥30 kg/ m 2 and a body surface area (BSA) ≥2 m 2 . Dose reductions occurred in 16.1% of patients with a BMI ≥30 kg/m 2 and 32.4% with BMI ≥ 30kg/m 2 and BSA ≥2 m 2 , respectively. In patients with BMI ≥30 kg/m 2 , multivariate analysis demonstrated a trend towards better RFS in the fully dosed com- pared to the dose-reduced group (Hazard ratio (HR): 0.69, 95% CI: 0.43-1.09; p = 0.11); however, there was no statistically significant difference in OS. In patients with BMI ≥30 kg/m 2 and BSA ≥2 m 2 , multivariate analysis demonstrated better RFS in fully dosed compared with dose-reduced patients (HR: 0.48, 95% CI: 0.27-0.85; p = 0.01) and a strong trend towards better OS (HR: 0.53, 95% CI: 0.28-1.01; p = 0.052). This group com- prised predominantly of men. CONCLUSIONS Data support the recommendation

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Progression-Free Survival at 24 Months and Subsequent Outcomes for Patients With DLBCL Annals of Oncology Take-home message • This analysis of the SEAL database was designed to evaluate outcomes among patients with diffuse large B-cell lymphoma (DLBCL) who had attained PFS at 24 months (PFS24). • Patients treated with rituximab-based chemoimmunotherapy on clinical trials who achieved PFS24 had outcomes similar to those of the age-, gender-, and country-matched background population for 7 years after PFS24. Neil Majithia MD Abstract BACKGROUND Patients with diffuse large B-cell lymphoma treated with first-line anthracycline based immunochemotherapy and remaining in remission at two years have excellent out- comes. This study assessed overall survival (OS) stratified by progression-free survival at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the SEAL collaboration. PATIENTS AND METHODS PFS24 was defined as being alive and progression-free 24 months after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared to each patient's age-, sex-, and country-matched gen- eral population using expected survival and standardized mortality ratios (SMRs). RESULTS 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18-92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. 1423 evaluable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8-8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI: 30.0-34.4). 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI: 1.09-1.37). The observed OS versus expected OS at 3, 5, and 7 years after achiev-

Immune Recognition of SomaticMutations Leading to CompleteDurable Regression in Metastatic Breast Take-home message • In this case study of a patient with chemo-refractory HR-positivemetastatic breast cancer, treatment with tumor- infiltrating lymphocytes reactive against four mutated proteins in combination with IL-2 and checkpoint blockade led to complete durable regression of disease, ongoing for over 22 months. • These results demonstrate a new immunotherapeutic approach for these patients. Abstract Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as mela- noma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithe- lial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1-7. Adoptive transfer of autologous lym- phocytes that specifically target proteins encoded by somatically mutated genes has mediated sub- stantial objective clinical regressions in patients with metastatic bile duct, colon and cervical can- cers8-11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lym- phocytes (TILs) reactive against mutant versions of four proteins-SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-pro- tein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients. Immune Recognition of Somatic Mutations Lead- ing to Complete Durable Regression in Metastatic Breast Cancer. Nat Med 2018 Jun 01;24(6)724-730, N Zacharakis, H Chinnasamy, M Black, et al. www.practiceupdate.com/c/69774 Cancer Nature Medicine

ing PFS24 was 93.1% vs. 94.4%, 87.6% vs. 89.5%, and 80.0% vs. 83.7%, respectively. CONCLUSION Patients treated with rituximab containing anthracycline-based immuno- chemotherapy on clinical trials who are alive without progres- sion at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clini- cally indistinguishable from the age-, sex-, and country-matched background population for seven years after achieving PFS24. Progression-Free Survival at 24 Months (PFS24) and Sub- sequent Outcome for Patients With Diffuse Large B-Cell Lym- phoma (DLBCL) Enrolled on Randomized Clinical Trials. Ann Oncol 2018 Jun 12;[EPub Ahead of Print], MJ Maurer, TM Haber- mann, Q Shi, et al. www.practiceupdate.com/c/69589

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Sunitinib Alone or After Nephrectomy in Renal Cell Carcinoma The New England Journal of Medicine Take-home message • This phase III trial assessed the role of nephrectomy in 450 patients with confirmed intermediate- or poor-risk metastatic clear- cell renal-cell carcinoma at presentation who either underwent nephrectomy and then sunitinib or sunitinib alone. The median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy/sunitinib group with regard to overall survival (stratified HR for death, 0.89). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy/sunitinib group. No significant differences in response rate or progression-free were observed. • The authors concluded that sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. Jeffrey Wiisanen MD Abstract

COMMENT By Bradley G Somer MD

BACKGROUND Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. METHODS In this phase III trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS A total of 450 patients were enrolled fromSeptember 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-su- nitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confi- dence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant dif- ferences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. CONCLUSIONS Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor- risk disease. Sunitinib Alone or After Nephrectomy in Met- astatic Renal-Cell Carcinoma. N Engl J Med 2018 Jun 03;[EPub Ahead of Print], A Méjean, A Ravaud, S Thezenas, et al. www.practiceupdate.com/c/69138

Cytoreductive Nephrectomy – The Important CARMENA Trial F or decades, based on antiquated data in patients receiving interferon alfa, we have been performing cytoreductive nephrectomy in patients with metastatic disease almost routinely despite multiple new therapies emerging, which have had an enormous impact on outcome for patients with metastatic RCC. The ques- tion remained whether cytoreductive nephrectomy worked to extend survival even in the modern era of metastatic RCC. Until now, there was no evidence to direct us one way or another. There have been numerous large retrospective series emerging, showing that those who received cytoreductive nephrectomy did better, reinforcing the mantra that this treatment works to extend survival in the setting of metastases. Yet, despite voluminous data, it was suspected that there was some selection bias for surgery within the retrospective datasets. So, many argued that, except for those who need treatment emergently, generally speaking, cytoreductive nephrectomy remained a standard. Moreover, for many years, clinical trials for patients with meta- static disease excluded patients who didn’t have a nephrectomy. However, with the prospective CARMENA data presented at ASCO 2018 by Dr. Méjean and with publi- cation in NEJM , this thinking has changed overnight. CARMENA is a phase III trial of patients with metastatic clear cell carcinoma, with MSKCC intermediate- and poor-risk disease who were randomized to sunitinib alone vs cytoreductive nephrectomy followed by sunitinib (standard dosing). A total of 450 patients were enrolled, with a median follow-up of 50.9 months. Sunitinib alone was noninferior to nephrectomy followed by sunitinib. Median OS was 18.4 months with sunitinib alone and 13.4 months with nephrectomy followed by sunitinib. This clearly means that, for those in this risk group who are going on treatment, cytoreductive nephrectomy is inappropriate. This calls to question, what about good-risk patients? That remains unanswered. Additionally, what if a checkpoint inhibitor or combination therapy is used in the front line? Likely, the principle should stand, and cytoreductive nephrectomy should be abandoned in that setting. The importance of this trial is that we can now definitively say that cytoreductive nephrectomy is inappropriate in most clinical settings of metastatic RCC.

Dr. Somer is an Assistant Professor of Hematology/Oncology at the University of Tennessee Health Science Center, and Senior Partner at the West Clinic in Memphis, Tennessee.

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Circulating Tumor Cell Status Predicts Radiotherapy Benefit in Early Breast Cancer JAMA Oncology

COMMENT By Lee S Schwartzberg MD, FACP I ncreasingly sensitive biomarkers have the potential to stratify patients with early-stage breast cancer (ESBC) into groups that are at higher risk of relapse, raising the possibility of select- ing such patients for more aggressive treatment. Circulating tumor cells (CTCs) have been shown in multiple studies to be prognostic for relapse-free survival in ESBC and are easily obtained via com- mercially available means. The use of this biomarker to determine outcome for locoregional therapies has not pre- viously been reported. Goodman et al assessed two large cohorts, the National Cancer Data Base and a prospective clinical trial called SUCCESS, to determine the influence of positive CTCs on outcome when RT was given or not. In both cohorts, patients who were CTC-positive and received RT had improved survival compared with those who were CTC-positive and did not receive RT. CTC-negative patients had similar outcomes with or without RT. Outcome results in the CTC+/RT+ group were superior whether examined for disease-free survival, locoregion- al-free survival, or overall survival. An intriguing finding in this analysis was theadvantagewithRTappearedconfined only to ESBC patients who underwent breast-conserving surgery. Patients in the CTC+ subgroup who underwent mastec- tomy did not have better outcomes. Do CTCs serve as a surrogate for residual disease in the breast as well as a marker of systemic micrometastasis? Or do CTCs preferentially reside in the breast tissue, making them more susceptible to a course of RT? The biology remains to be elucidated, but this provocative finding should be addressed with a randomized clinical trial. From a clinical perspective, identi- fying a high-risk subgroup for RT within a broader set in whom de-escalation of treatment has been generally shown to be effective (age >65–70; ER+/HER2−) would further personalize breast cancer treatment and target treatment to those who will benefit.

Take-home message • In this cohort study of 1697 patients from a large national database and 1516 patients from a randomized clinical trial with early-stage breast cancer who were evaluated for circulating tumor cell status, patients with at least one circulating tumor cell and who received radiotherapy after breast-conserving surgery had significantly longer local recurrence-free survival, disease-free survival, and overall survival compared with those who did not receive radiotherapy. Patients without circulating tumor cells did not experience longer survival outcomes after radiotherapy. • Circulating tumor cell status might be an important predictive clinical marker for the benefit of radiotherapy in patients with early-stage breast cancer. Abstract

cohort (4-year OS, 94.9% for CTC-positive RT vs 88.0% for CTC-positive non-RT vs 93.9% for CTC-negative RT vs 93.4% for CTC-negative non-RT groups; P< .001) and 5-year DFS within the SUCCESS cohort (88.0% for CTC-positive RT vs 75.2% for CTC-positive non-RT vs 92.3% for CTC-negative RT vs 88.3% for CTC-nega- tive non-RT; P = .04). In the NCDB cohort, RT was associated with longer OS in patients with CTCs (time ratio [TR], 2.04; 95% CI, 1.55-2.67; P< .001), but not in patients without CTCs (TR, 0.80; 95% CI, 0.52-1.25; P= .33). In the SUCCESS cohort, CTC-positive patients treated with RT exhibited longer LRFS (TR, 2.73; 95% CI, 1.62- 4.80; P< .001), DFS (TR, 3.03; 95% CI, 2.22-4.13; P < .001), and OS (TR, 1.83; 95% CI, 1.23-2.72; P = .003). Among patients from both cohorts who underwent breast-conserving surgery, RT was associated with longer OS in patients with CTCs (TR, 4.37; 95% CI, 2.71-7.05; P< .001) but not in patients without CTCs (TR, 0.87; 95% CI, 0.47-1.62; P= .77). Radiotherapy was not associ- ated with OS after mastectomy in CTC-positive or CTC-negative patients. CONCLUSIONS AND RELEVANCE Treatment with RT was associated with longer LRFS, DFS, and OS in patients with early-stage breast can- cer and detectable CTCs. These results are hypothesis generating; a prospective trial eval- uating CTC-based management for RT after breast-conserving surgery in women with ear- ly-stage breast cancer is warranted. Association of Circulating Tumor Cell Status With Benefit of Radiotherapy and Survival in Early-Stage Breast Cancer. JAMA Oncol 2018 May 03;[EPub Ahead of Print], CR Goodman, B-L L Seagle, TWP Friedl, et al. www.practiceupdate.com/c/67675

IMPORTANCE Circulating tumor cells (CTCs) rep- resent the liquid component of solid tumors and are a surrogate marker for residual cancer burden. Although CTC status is prognostic of recurrence and death in breast cancer, its role in guiding clinical management remains unknown. OBJECTIVE To determine whether CTC status is predictive of radiotherapeutic benefit in ear- ly-stage breast cancer. DESIGN, SETTING, AND PARTICIPANTS The cohort studies in the present analysis included patients with stages pT1 to pT2 and pN0 to pN1 breast cancer and known CTC status from the National Cancer Database (NCDB) and the multicenter phase 3 SUCCESS clinical trial. Multivariable parametric accelerated failure time models were used to evaluate the association of CTC status and radiotherapy (RT) with survival out- comes. Data were collected from January 1, 2004, through December 31, 2014, from the NCDB cohort. The SUCCESS trial collected data from September 1, 2005, through September 30, 2013. The analyses were completed from November 1, 2016, through December 17, 2017. EXPOSURE Adjuvant RT. MAIN OUTCOMES AND MEASURES Overall survival (OS), local recurrence-free survival (LRFS), and disease-free survival (DFS). RESULTS A total of 1697 patients from the NCDB (16 men [0.9%] and 1681 women [99.1%]; median age, 63 years; interquartile range, 53-71 years) and 1516 patients from the SUCCESS clinical trial (median age, 52 years; interquartile range, 45-60 years) were identified. Circulating tumor cells were detected in 399 patients (23.5%) in the NCDB cohort and 294 (19.4%) in the SUC- CESS cohort. The association of RT with survival was dependent on CTC status within the NCDB

" From a clinical perspective, identifying a high-risk subgroup for RT within a broader set in whom de-escalation of treatment has been generally shown to be effective (age >65–70; ER+/ HER2−) would further personalize breast cancer treatment and target treatment to those who will benefit. "

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