PracticeUpdate: Haematology & Oncology | Vol 1.No.3 - 2016

VOL. 1 • No. 3 • 2016

RESEARCH NEWS AND VIEWS FROM ELSEVIER

FORMERLY HAEMATOLOGY & ONCOLOGY NEWS

BREAST A negative margin of 2 mm is the desired standard for DCIS treated with WBRT due to a low rate of IBTR and need for further surgery 8 SKIN Limited studies evaluate the benefits of skin cancer screening. Future research needs to evaluate screening of persons at high risk and effect of screening on melanoma- specific mortality rates 10 HAEMATOLOGY Ipilimumab is active in patients with relapse of haematologic cancers after allogeneic HSCT, but some patients experience GVHD or immune-related adverse events 12 IASLC 2016 Follow the 7th Latin American Conference on Lung Cancer as the news rolls in on www.PracticeUpdate.com There is an appreciation that probably about 10%of menwith advanced prostate cancer have DNA- repair gene defects, and BRCA2 is the most common. BRCA1 and BRCA2 are themajority, but also there are some ATMand other genes as well. Dr Oliver Sartor 15 Readers Poll What’s the ONE medical app you can’t live without? Scan this code or go to http://goo.gl/XuJZdP to have your say in this issue’s PracticeUpdate Haematology & Oncology Readers Poll. OPINION

The ever changing landscape for prostate cancer care in Australia

Following the US recommendation in 2012 against PSA testing for prostate cancer, there has been a drop in the incidence of prostate cancer, PSA testing and a reduction in radical prostatectomies. Urological surgeons at the Royal Melbourne Hospital, Dr Homi Zargar and Dr Rajesh Nair discuss this impact locally and how robotic surgery and new research in prostate cancer are likely to impact clinical practice in Australia. 4

Robot-assisted laparoscopic prostatectomy vs open radical retropubic prostatectomy The Lancet Robot-assisted laparoscopic radical prostatectomy is associated with clinical outcomes similar to those achieved with open radical prostatectomy.

Prevalence of ESR1 mutations in cell- free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial JAMA Oncology In patients with ER-positive breast cancer treated with aromatase inhibitors, ESR1 mutations are prevalent, with increased disease aggressiveness associated with Y537S and D538G mutations. 9

Improved outcomes with carfilzomib compared with bortezomib in relapsed multiple myeloma regardless of prior treatment Leukemia Compared with bortezomib, treatment with carfilzomib improves outcomes in patients with relapsed multiple myeloma regardless of prior exposure to bortezomib or lenalidomide or the number of prior treatment lines. 13

A comparison of survival by site of metastatic resection in metastatic colorectal cancer Clinical Colorectal Cancer

Patients undergoing MR for lung and locoregional disease experienced a similar survival benefit compared with patients undergoing MR for liver-limited disease. 14

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EXPERT OPINION Proteosome inhibitors in advanced castrate-resistant prostate cancer Interview with Guru Sonpavde, MD

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

Dr Sonpavde, Associate Professor of Medicine, UAB School of Medicine in Alabama, discusses the novel proteasome inhibitors and where this class of drug would fit in the spectrum of treatment for advanced prostate cancer.

Dr Haffizulla: I know that you are the principal investigator for an upcom- ing clinical trial, and probably the date will mature in the next couple of years or months. The trial concerns proteasome inhibitors, especially

carfilzomib and its place in the spec- trum of treatment in prostate cancer. Can you tell me a little bit more about this particular class of drugs? Dr Sonpavde: This is a novel class of compounds to be looked at in ad- vanced castrate-resistant prostate cancer. Proteasome inhibitors, of course, are widely used in multiple myeloma, or haematologic malig- nancy. There is rationale to look at them in advanced prostate cancer. More than a decade ago, bortezomib was the first in class proteasome in- hibitor also approve in myeloma. It was looked at in a phase 1 trial that included solid tumours, and there was deep activity in a small subset of patients with advanced castrate- resistant prostate cancer. That

included tumour tissue responses, regressions, and PSA declines. That was a small subset, but the responses were deep. So we believe that there might be even better activity with carfilzomib, which is a more potent irreversible proteasome inhibitor, in patients with this disease. We have a phase 2 trial ongoing looking at this. Dr Haffizulla: Where do you think that would fit into the spectrum of treatment for advanced prostate cancer, specifically castrate-resistant prostate cancer? Dr Sonpavde: One of the things that we are still learning is that, despite all of the agents that are out now, including enzalutamide and abira- terone, which are novel androgen pathway-inhibiting drugs, they’re active, but there is a ton of cross-re- sistance. The patients who progress on abiraterone, or enzalutamide, when switched to the other drug, don’t have a huge response rate. The response rate is in the 20% to 30% range. So we need new classes of agents for these patients who are progressing after these novel agents, because of the cross-resistance. There could be a big draw for a new class of agents in these patients who progress after abiraterone, or enzalutamide, or both. There could be a big draw for a new class of agents in these patients who progress after abiraterone, or enzalutamide, or both.

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View the full interview with Dr Guru Sonpavde

JOURNAL SCAN Conventional vs hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer The Lancet Oncology Take-home message • This phase 3 noninferiority study enrolled 3216 men with localised prostate cancer who were randomised 1:1:1 to receive conventional radiotherapy (74 Gy in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks). At 5 years, the proportion of patients who were clinically or biochemically failure-free were comparable between patients receiving 60 Gy and the conventional 74 Gy (90.6% and 88.3%, respectively), and the two schedules were noninferior; however, 57 Gy (85.9 % of patients failure-free) was not noninferior to 74 Gy. Side effects were similar between conventional and hypofractionated treatment groups based on clinician- and patient-reported outcomes. • The authors recommend hypofractionated radiotherapy at 60 Gy over 20 fractions as a new standard of care for radiotherapy in patients with localised prostate cancer given that it is noninferior to the conventional 74 Gy in 37 fractions.

Abstract BACKGROUND Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advan- tage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a ran- domised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. METHODS CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b- T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated sched- ules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neo- adjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Compre- hensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non- inferiority was 1.208. Analysis was by intention to treat. Long-term follow-up continues. FINDINGS Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62.4

and bladder adverse events was 13.7% (111 events) and 9.1% (66 events) in the 74 Gy group, 11.9% (105 events) and 11.7% (88 events) in the 60 Gy group, 11.3% (95 events) and 6.6% (57 events) in the 57 Gy group, respectively. No treatment- related deaths were reported. INTERPRETATION Hypofractionated radio- therapy using 60 Gy in 20 fractions is non-inferior to conventional fractiona- tion using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Conventional versus hypofraction- ated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial . Lancet Oncol 2016;17:1047–1060, Dearnaley D, Syndikus I, Mossop H, et al.

months (IQR 53.9–77.0). The propor- tion of patients who were biochemical or clinical failure free at 5 years was 88.3% (95% CI 86.0–90.2) in the 74 Gy group, 90.6% (88.5–92.3) in the 60 Gy group, and 85.9% (83.4–88.0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0.84 [90% CI 0.68–1.03], pNI=0.0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1.20 [0.99–1.46], pNI=0.48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year inci- dence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel

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The ever changing landscape for prostate cancer care in Australia

Interview with Dr Homayoun (Homi) Zargar, MD, FRACS (Urol)

Urological surgeons Dr Homi Zargar and Dr Rajesh Nair give PracticeUpdate a review of clinically relevant new research in prostate cancer, focusing on those that could potentially impact clinical practice in Australia. PSA testing in Australia

and Dr Rajesh Nair, FRCS (Urol), FEBU, MSc

The STAMPEDE trial STAMPEDE is a randomised controlled trial using a multi-arm, multi-stage platform design. It recruited 2962 men with high-risk localised (24%), node-positive (15%) or metastatic prostate cancer (61%) to four separate treatment arms: ADT alone, ADT plus zoledronic acid, ADT plus docetaxel, or ADT plus zoledronic acid and docetaxel. 6 The addition of docetaxel demonstrated sig- nificance in both its primary endpoint of overall survival (77 vs 67 months; P = 0.003) and sec- ondary endpoint of failure-free survival (37 vs 21 months; P < 0.0001) compared with ADT alone. Thus, docetaxel with standard therapy improved overall survival by an average of 10 months in men with newly diagnosed, hormone-naive, advanced prostate cancer. For the subset of patients with metastatic disease, the average improvement in overall survival was even higher at 22 months. Adding zoledronic acid to standard therapy did not affect survival, and adding the combination of zoledronic acid and docetaxel was not more effective than adding docetaxel alone. What does the future hold? We need to identify men with prostate cancer early. With further development of technology, hopefully we can utilise imaging in conjunction with PSA testing for identifying and stratifying patients with prostate cancer. More sophisticated imaging in combination with genomic markers can help identify patients who might benefit from lymph node dissection and assist in the adoption of patient-specific lymph node dissection tem- plate. Image-guided surgery holds the promise of identifying cancer margins intraopertively. Genomics can play a significant role in stratify- ing patients according to their risk, differentiating men presenting with similar diagnostic results but having different cancer biology. So genomic tests can guide us in the better identification of patients requiring early treatment and in the modification of treatment depending on the patient’s genetic makeup, as part of our quest toward delivering precision medicine. References 1. Moyer VA; US Preventive Services Task Force. Ann Intern Med 2012;157:120-134 2. Weiner AB, Matulewicz RS, Eggener SE, et al. Prostate Cancer Prostatic Dis 2016 Jul 19. doi: 10.1038/pcan.2016.30. [Epub ahead of print] 3. Yaxley JW, Coughlin GD, Chambers SK, et al. Lancet 2016 July 26. doi: 10.1016/S0140-6736(16)30592-X. [Epub ahead of print] 4. Van Leeuwen P, Emmeett L, Ting F, et al. BJU Int 2016 May 21. doi: 10.1111/bju.13540. [Epub ahead of print] 5. Sweeney CJ, Chen YH, Carducci M, et al. N Engl J Med 2015;373:737-746 6. James ND, Sydes MR, Clarke NW, et al. Lancet 2016;387:1163-1177

those achieved with open radical prostatectomy. Yet, secondary outcomes show a different picture: RARP patients demonstrate less blood loss (443 vs 1338 ml, P = 0.001), less postoperative pain and a shorter hospital stay (1.5 vs 3.2 days, P = 0.0001) compared with ORP patients. While a highly commendable study, there are a number of methodological oversights which are unlikely to see a change in the number of RARPs performed in Australia or worldwide. This study does not control for individual surgical experience, trainee involvement, and outcome parameters re- corded at 12 weeks represent too short a follow-up period to allow for meaningful comparison. If any- thing, this study allows one to view robotic surgery in a favourable light. A lesser-experienced surgeon can deliver functional and oncological outcomes that an experienced open surgeon can deliver by adopting robotic techniques. (See page 5.) Australia has led the charge in the research and utilisation of [ 68 Ga]gallium-labelled prostate- specific membrane antigen ligand ( 68 Ga-PSMA) positive emission tomography (Ga-PSMA PET/ CT). There is an increasing bank of evidence demonstrating that Ga-PSMA PET can present lesions suspicious for prostate cancer with excel- lent contrast and a high detection rate even when the level of prostate specific antigen is low. Van Leeuven and colleagues from Sydney recently reported 300 consecutive patients with prostate cancer; 70 of whom developed biochemi- cal recurrence following radical prostatectomy. Those with a PSA of ≥ 0.05 and <1.0 ng/mL underwent Ga-PSMA-PET/CT. 4 They demonstrated that Ga-PSMA-PET/CT in patients with intermediate or high-risk prostate cancer has 95% specificity and 64% sensitivity for detecting lymph node metastases. Even at PSA levels <0.5 ng/mL, it appears to be useful for re-staging of prostate cancer in patients with rising PSA levels who are being considered for salvage radiotherapy. Managing metastatic prostate cancer The sands are shifting in the way patients with metastatic prostate cancer are managed. The CHAARTED 5 and STAMPEDE 6 trials demon- strated significant survival advantages with the addition of upfront chemotherapy to traditional androgen deprivation therapy (ADT) when man- aging these patients. The CHAARTED trial The Eastern Cooperative Oncology Group (ECOG) phase 3 randomised CHAARTED trial evaluated whether the addition of upfront chemotherapy to ADT improved overall survival in patients with hormone-sensitive metastatic prostate cancer. A total of 790 patients diagnosed with hormone-sensitive metastatic prostate can- cer were randomised to ADT alone vs ADT with the addition of docetaxel at a dose of 75 mg/m 2 every 3 weeks for 6 cycles started within 4 months of the initiation of ADT. 5 The results reported were in favour of adding docetaxel to ADT in men with hormone-sensitive metastatic prostate cancer. ADT plus docetaxel re- sulted in a median overall survival of 57.6 months (P = 0.0003) compared with 44 months in the ADT-alone arm. In stratifying the patients accord- ing to high vs low-volume disease, the benefit for docetaxel therapy was found to be more apparent in the high-volume metastatic group. 68 Ga-PSMA positive emission tomography in prostate cancer

In 2012, on the back of two large randomised trials – the Prostate, Lung, Colorectal and Ovar- ian cancer screening study (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial – the US Preven- tive Services Task Force issued a recommenda- tion against prostate-specific antigen (PSA)-based screening for prostate cancer. It suggested that the potential harms of PSA-testing outweighed the benefits offered by curative prostate cancer care. 1 Following this recommendation, a drop in PSA testing and overall prostate cancer incidence was observed in the US, which translated to a reduction in radical prostatectomies there.

Genomic tests can guide us in the better identification of patients requiring early treatment and in the modification of treatment depending on the patient’s genetic makeup, as part of our quest toward delivering precision medicine.

In Australia, a similar decline in rates of PSA testing has been observed since 2012 following the widely publicised USPSTF recommendation. It remains to be seen whether this translates to a reduction in the number of local treatments. A controversial study evaluating the increasing incidence of metastatic prostate cancer in the United States was reported by Weiner and col- leagues. 2 His group evaluated the role of relaxed screening following the USPSTF recommenda- tions and whether this led to changes in the incidence of advanced and metastatic prostate cancer at diagnosis. All men diagnosed with prostate cancer in the National Cancer Data Base (2004–2013) at 1089 different healthcare facilities in the US were evaluated. The annual incidence of metastatic prostate cancer increased by 72% from 2007 to 2013. The greatest (92%) increase in metastatic prostate cancer was seen in men aged 55–69 years. These results did not take into account a num- ber of confounding events and observations. For example, changes in aggregate screening before the USPSTF recommendations, alterations in the biological aggressiveness of prostate cancer, and improved sensitivity and use of imaging when iden- tifying those patients with metastatic disease were not accounted for. It is unlikely that these results are transferrable to anAustralian population where PSA screening has always remained opportunistic. Robot-assisted laparoscopic prostatectomy vs open radical retropubic prostatectomy There has been a significant lack of data com- paring robot-assisted laparoscopic radial prosta- tectomy (RARP) and open radical prostatectomy (ORP). Yaxley et al from Queensland reported the early oncological and functional outcomes following a randomised controlled multicentre phase 3 study published in The Lancet this year. 3 A total of 326 patients with newly diagnosed localised prostate cancer were randomised to RARP and ORP. Primary outcome parameters reported included urinary and sexual function, and oncological outcomes determined by surgical margin status, and evidence of disease progression at 6 and 12 weeks post operatively. Urinary function and sexual function were simi- lar at 12 weeks post prostatectomy. Positive surgical margin rates were also similar at 10% vs 15% in the ORP vs RARP groups, respectively (P = 0.0021). Robot-assisted laparoscopic radical prostatectomy is associated with clinical outcomes similar to

Dr Zargar is a urological surgeon with fellowship training in uro-oncology and advanced laparoscopic and robotic surgery. He is Consultant Urologist at the Royal Melbourne Hospital and Senior Clinical Lecturer, Department of Surgery at the University of Melbourne. Dr Nair is a UK-trained urological surgeon undergoing advanced fellowship training in robotics and uro-oncology at the Royal Melbourne Hospital.

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Robotic equals open surgery for prostate cancer Comment by Thomas Guzzo, MD, MPH T his is the first published randomised trial comparing outcomes between robotic and open prostatectomy for men with The robotic patients did have significantly less blood loss, a shorter length of stay, and were less likely to have had an intraoperative adverse event.

prostate cancer. The study included 308 men undergoing surgery at a single centre. The au- thors report no significant differences in short- term urinary and sexual function outcomes at 6 and 12 weeks. There was also no significant difference in positive margin rates between surgical approaches.

With the widespread adoption of robotic surgery in the United States over the last dec- ade, this trial is unlikely to have a significant impact on practice patterns. This study does potentially validate what we have already ob- served clinically: regardless of approach, pros- tatectomy functional and oncologic outcomes are equivalent and more dependent on surgeon expertise and experience than a machine. It also demonstrates the potential short-term the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74.50 vs 71.10; P = 0.09) or 12 weeks post-surgery (83.80 vs 82.50; P = 0.48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatecto- my group at 6 weeks post-surgery (30.70 vs 32.70; P = 0.45) or 12 weeks post-surgery (35.00 vs 38.90; P = 0.18). Equivalence testing on the difference be- tween the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Δ of 10%. However, a superiority test showed that the two proportions were not significantly different (P = 0.21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot- assisted laparoscopic prostatectomy group had postoperative complications (P = 0.052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted lapa- roscopic prostatectomy experienced intraoperative adverse events. INTERPRETATION These two techniques yield simi- lar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet 2016 Jul 26;[EPub Ahead of Print], JW Yaxley, GD Coughlin, SK Chambers, et al.

There is a significant methodologic flaw that limits our ability to draw definitive conclusions from this study.

Robot-assisted laparoscopic prostatectomy vs open radical retropubic prostatectomy The Lancet Take-home message

• This randomised, multicentre phase 3 trial compared clinical outcomes of open vs robot-assisted laparoscopic radical prostatectomy in 326 men with newly diagnosed early-stage prostate cancer. Urinary function and sexual function were similar at 12 weeks post resection. Positive surgical margin rates were also similar at 10% vs 15% in the open vs robot-assisted laparoscopic prostatectomy groups, respectively (P = 0.21). • Robot-assisted laparoscopic radical prostatectomy is associated with clinical outcomes similar to those achieved with open radical prostatectomy. Abstract

benefits of robotic surgery including less blood loss, less pain, and a shorter hospital stay. However, I would caution readers when interpreting these results that, in my opinion, there is a significant methodologic flaw that limits our ability to draw definitive conclusions from this study. As noted in the methods sec- tion, this study was performed by two surgeons (one robot and one open) and therefore has questionable generalisability to all urologists who perform prostate cancer surgery. Addition- ally, at the start of the trial, the robotic surgeon had only completed 200 robotic prostatecto- mies compared with the open surgeon who had 15 years’ post-fellowship experience and had already completed 1500 open prostatec- tomies. With all due respect to both surgeons, I am not sure that this was a fair comparison.

the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgi- cal margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health-related and domain- specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. FINDINGS Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prosta- tectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radi- cal retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot-assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between

BACKGROUND The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to com- pare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. METHOD In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women’s Hospital (Brisbane, QLD). Participants were ran- domly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer gen- erated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient’s condi- tion. Further, a masked central pathologist reviewed

Dr Guzzo is Assistant Professor of Urology in Surgery, University of Pennsylvania Perelman Center for Advanced Medicine.

JOURNAL SCAN Improved outcomes with early salvage radiotherapy inmen with detectable PSA after prostatectomy for prostate cancer Journal of Clinical Oncology Take-home message • Salvage radiotherapy outcomes were examined in 1106 men with detectable PSA after radical prostatectomy for prostate cancer. At a median follow-up of 8.9 years, tumour stage, Gleason score, and pre-salvage radiotherapy PSA correlated with overall survival, cumulative incidence for biochemical recurrence (BcR), distant metastases, and cause-specific mortality on multivariate analyses. The risks of BcR, distant metastases, and cause-specific and all-cause mortality were significantly increased with each doubling of pre-radiotherapy PSA. • Reductions in BcR, metastases, and mortality may be achieved by using salvage radiotherapy at lower PSA levels. The authors argue against prolonged monitoring of PSA levels that delays the start of salvage radiotherapy after prostatectomy. Abstract

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0.001), DM (HR, 1.32; P < 0.001), CSM (HR, 1.40; P < 0.001), and all-cause mortality (HR, 1.12; P = 0.02). Using a pre-SRT PSA cutoff ≤ 0.5 versus > 0.5 ng/mL, 5-year and 10-year cumulative incidences for BcR were 42% versus 56% and 60% versus 68% (P < 0.001), DM 7% versus 14% and 13% versus 25% (P < 0.001), CSM 1% versus 4% and 6% versus 13% (P < 0.001), and OS of 94% versus 92% and 83% versus 73% (P > 0.05). CONCLUSION SRT outcomes are in part affected by factors associated with prostatectomy findings but may be posi- tively affected by using SRT at lower PSA levels, including reductions in BcR, DM, CSM, and all-cause mortality. These findings argue against prolonged monitoring of detectable postprostatectomy PSA levels that delay initiation of SRT. Improved metastasis-free and survival outcomes with early salvage radiotherapy in men with detectable prostate-specific antigen after prostatectomy for prostate cancer. J Clin Oncol 2016 Aug 01;[Epub ahead of print], Stish BJ, Pisansky TM, Harmsen WS, et al.

PURPOSE To describe outcomes of salvage radiotherapy (SRT) for men with detectable prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer and identify as- sociations with outcomes. PATIENTS AND METHODS A total of 1,106 patients received SRT between January 1987 and July 2013, with median follow-up 8.9 years. Outcomes were estimated using Kaplan-Meier for overall survival (OS) and cumulative incidence for biochemical recurrence (BcR), distant metastases (DM), and cause-specific mortality (CSM). Variable associations with outcomes used Cox or Fine-Gray methods, as appropriate. Multiple variable analyses used backward selection with P < 0.05 for retention. RESULTS In multiple variable analyses, pathologic tumour stage, Gleason score, and pre-SRT PSA were associated with BcR, DM, CSM, and OS; androgen suppression and SRT doses > 68 Gy were associated with BcR; and age was associated with OS. Each pre-SRT PSA doubling increased significantly the relative risk of BcR (hazard ratio [HR], 1.30; P <

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MINIMUM PRODUCT INFORMATION: PALEXIA ® SR (tapentadol hydrochloride) INDICATION: Moderate to severe chronic pain unresponsive to non-narcotic analgesia. CONTRAINDICATIONS: Known hypersensitivity to tapentadol or any component of Palexia SR; conditions in which mu-opioid receptor agonist activity is contraindicated e.g. significant respiratory depression and acute or severe bronchial asthma or hypercapnia; confirmed or suspected paralytic ileus; acute intoxication with alcohol; hypnotics, centrally acting analgesics or psychotropic drugs; patients who are receiving MAO inhibitors or who have taken them within the last 14 days. PRECAUTIONS: Monitor for signs of abuse and addiction; repeated administration may lead to tolerance; withdrawal symptoms could occur after abrupt discontinuation; not recommended in patients with increased intracranial pressure, impaired consciousness, or coma and severe renal or severe hepatic impairment; caution in patients with impaired respiratory functions, patients with head injury, brain tumours, a history of seizures or any condition that increases risk of seizures, moderate hepatic impairment or biliary tract disease, including acute pancreatitis. Use in pregnancy (Category C). Should not be used during breastfeeding. Not recommended for children <18 years old. May impair ability to drive or operate machinery. INTERACTIONS: Care should be taken when combining with mixed opioid agonist/antagonists or partial mu-opioid agonists; additive CNS depression with concomitant administration of other mu-opioid receptor agonist PBS Information: Restricted benefit. Chronic severe disabling pain not responding to non-narcotic analgesics. Authority required for increased maximum quantities and/or repeats. Refer to PBS schedule for full restricted benefit and authority information. Before prescribing, please review the Product Information available at www.seqirus.com.au/PI.

For Chronic Pain Patients Pain relief as effective as oxycodone CR with significantly less constipation, nausea and vomiting (p<0.001)* 1,2 *Meta-analysis to assess non-inferior efficacy and superior GI tolerability (constipation) in moderate to severe chronic pain; PALEXIA SR 100–250 mg BD vs. oxycodone CR 20–50 mg BD That’s just one of the ways PALEXIA SR helps you do more for your patients with moderate to severe chronic pain

analgesics, general anaesthetics, phenothiazines, other tranquilisers, sedatives, hypnotics or other CNS depressants (including alcohol and illicit drugs) – reduction of dose of one or both agents should be considered; contraindicated in patients who are receiving MAO inhibitors or who have taken them within the last 14 days; isolated case reports of serotonin syndrome when used in combination with serotonergic drugs (see full PI). ADVERSE EFFECTS: Very common ( ≥ 1/10): dizziness, somnolence, headache, nausea, constipation; Common ( ≥ 1/100 to <1/10): Decreased appetite, anxiety, depressed mood, sleep disorder, nervousness, restlessness, disturbance in attention, tremor, muscle contractions involuntary, flushing, dyspnoea, vomiting, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change, mucosal dryness, oedema. Postmarketing: suicidal ideation, angioedema, anaphylaxis and anaphylactic shock. DOSAGE AND ADMINISTRATION: To be taken orally twice daily, whole with sufficient liquid, approximately every twelve hours, with or without food. Initiation of therapy in patients currently not taking opioid analgesics: start with 50 mg Palexia SR twice daily. Initiation of therapy in patients currently taking opioid analgesics: nature, administration and mean daily dose of previous medication should be taken into account. Titration and maintenance: titrate individually to a level that provides adequate analgesia and minimises side effects under close supervision of prescribing physician; titration regimen in increments of 50 mg twice daily every 3 days shown to be appropriate in most patients in clinical trials. Total daily doses >500 mg not recommended. Discontinuation of treatment: taper dose gradually to prevent symptoms of withdrawal. Renal Impairment: not recommended in severe renal impairment. Hepatic Impairment: initiate at 50 mg once daily in moderate hepatic impairment; not recommended in severe hepatic impairment. Elderly patients more likely to have decreased renal and hepatic function – care in dose selection. Not recommended for use in children <18 years old. Based on approved Product Information dated 17 September 2015. REFERENCES: 1. Palexia SR Approved Product Information, 17 September 2015. 2. Lange B et al. Adv Ther 2010;27(6):381–99. PALEXIA ® SR is a registered trademark of Grünenthal Pty Ltd. PALEXIA ® SR is distributed by Seqirus (Australia) Pty Ltd under licence from Grünenthal Pty Ltd. Seqirus (Australia) Pty Ltd ABN 66 120 398 067, 63 Poplar Road Parkville, Victoria 3052. www.seqirus.com.au. Medical Information: 1800 642 865. Seqirus ™ is a trademark of Seqirus UK Limited or its affiliates. Date of preparation: September 2016. AUS/PALX/0616/0225. SEQP11124/HO/DPS. Ward6.

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Consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ Comment by Lee S Schwartzberg, MD, FACP O ne of the topics frequently discussed at multidisciplinary breast cancer tumour boards is how to handle patients who have DCIS with close or limited margins after lumpectomy. Many of these patients are considered for reoperation, adding morbidity and expense. The situation has been further complicated by recent consensus opinion that, for invasive breast cancer, no ink on tumour is acceptable, presuming patients will receive radiation therapy. We now have an important consensus statement on DCIS based on a thorough review of the available literature. The panel recommends a 2-mm margin for DCIS in order to reduce the risk of ipsilateral breast cancer recurrence to a minimum. Larger margins are not necessary. An excellent table in the paper addresses many of the clinical questions that frequently arise regarding benefit of radiation, endocrine therapy, and other common situations in the context of DCIS. This review is highly recommended for all breast surgeons and physicians who deal with this disease.

Society of Surgical Oncology – American Society for Radiation Oncology – American Society of Clinical Oncology consensus guideline onmargins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ Journal of Clinical Oncology Take-home message • The authors of this meta-analysis evaluated optimal margin width and ipsilateral breast tumour recurrence (IBTR) in patients with ductal carcinoma in situ (DCIS) treated with breast- conserving surgery and whole-breast irradiation (WBRT). Patients with negative margins have half the risk of IBTR seen in those with positive margins. The risk is again decreased by a 2-mm margin compared with smaller margins. Margins >2 mm are not associated with any added benefit in reducing IBTR. Re-excision should not be planned on negative margins <2 mm alone, and other factors should be considered. • A negative margin of 2 mm is the desired standard for DCIS treated with WBRT due to a low rate of IBTR and need for further surgery. In patients with smaller margins, clinicians need to consider each case individually when deciding on further excision. Abstract

More widely clear margins do not significantly decrease IBTR compared with 2 mm margins. Negative margins less than 2 mm alone are not an indication for mastectomy, and factors known to impact rates of IBTR should be considered in determining the need for re-excision. CONCLUSION The use of a 2 mm margin as the standard for an adequate margin in DCIS treated with WBRT is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcome, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins < 2 mm. J Clin Oncol 2016 Aug 15;[Epub ahead of print], Morrow M, Van Zee KJ, Solin LJ, et al.

BACKGROUND Controversy exists regarding the optimal negative margin width for ductal carcino- ma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation (WBRT). METHODS A multidisciplinary consensus panel used a meta-analysis of margin width and ip- silateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7883 patients and other published literature as the evidence base for consensus. RESULTS Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2 mm margin minimizes the risk of IBTR compared with smaller negative margins.

Dr Schwartzberg is a senior partner and Medical Director of the West Clinic, a 30-physician practice specialising in oncology, haematology and radiology located in Memphis, Tennessee.

Rate of distant metastases in women with breast carcinoma and an Oncotype DX recurrence score <18 Comment by Reshma L Mahtani, DO

JOURNAL SCAN Over-irradiation The Breast Take-home message

• This review discusses options for decreasing the radiation therapy burden for breast cancer patients. Abstract Decreasing the burden of radiation therapy (RT) for breast cancer includes, next to complete omission, several ways to tailor the extent of RT. Possible options for this include lowering of the total dose, such as selective omission of the boost, hypofractionated RT to shorten the duration of treatment, the selective introduction of partial breast irradiation and anatomy based target volume contouring to decrease the size of the irradiated volumes. Elective regional nodal irradiation showed in several randomised trials and meta-analyses to significantly impact on local-regional control, disease-free sur- vival, breast cancer mortality and overall survival. The generalisability of these re- sults remains complex in the light of the decreasing use of axillary lymph node dissection, the use of more effective adjuvant systemic therapy, the increas- ing use of primary systemic therapy and continuously improving RT techniques. In general, the use of RT compensates for the decreasing extent of surgery to the breast and the axillary lymph nodes, eliminating residual tumour cells while maintaining better aesthetic and functional results. In some occasions, however, the indications for the extent of RT have to be based on limited path- ological staging information. Research is ongoing to individualise RT more on the basis of biological factors including gene expression profiles. When consid- ering age, treatment decisions should rather be based on biological instead of formal age. The aimof this review article is to put cur- rent evidence into the right perspective, and to search for an appropriate appre- ciation of the balance between efficacy and side effects of local-regional RT. Breast 2016 Aug 10;[Epub ahead of print], Poortmans PMP, Arenas M, Livi L.

P atients in this analysis were considered low-risk on the basis of the traditional On- cotype DX classification (low, <18; intermediate, ≤ 31; high, >31) and overall had a very low risk of distant metastases, although follow-up was only 46 months. Of the 6 patients who recurred, 5 had a recurrence score (RS) between 11 and 17, and it should be noted that these patients would have been considered eligible for randomisation on the TAILORx study, as they would have been considered intermediate-, not low-risk ( Clin Breast Cancer 2006;7:347-350). We already have data for the low-risk group on TAILORx (<11); 99% of patients were free of breast cancer recurrence after 5 years of follow-up when treated with hormonal therapy alone. This study again highlights the need to obtain prospective data for patients with an intermediate score (11–25 by TAILORx criteria), and, therefore, the results of TAILORx patients in this subgroup are eagerly awaited.

Dr Mahtani is a haematologist/medical oncologist and Assistant Professor, Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami.

Breast carcinoma with an Oncotype Dx recurrence score <18: rate of distant metastases in a large series with clinical follow-up Cancer Take-home message

896 patients had an RS of 11–17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11–17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients). CONCLUSIONS The data from the current study docu- ment a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node- negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2016 Aug 15;[Epub ahead of print], Wen HY, Krystel-Whittemore M, Patil S, et al.

• This was a single-centre, retrospective study. The authors assessed the rate of development of distant metastases in 1406 women with early-stage ER-positive, HER2-negative breast cancer who had low recurrence scores on Oncotype DX testing. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. Only 6 patients (0.4%) developed distant metastases over a median follow-up of 46 months. The absolute rate of distant metastases among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years. • The rate of distant metastases over 5 years in women with early-stage ER+/HER2- breast cancer and low recurrence scores is 0.4%, although younger women have a higher rate of distant metastases. Abstract

chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. METHODS The authors reviewed the institutional data- base to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institu- tion between September 2008 and August 2013 and their 21-gene RS results. RESULTS A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0–10 and

BACKGROUND A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse tran- scriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)- positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

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Prevalence of ESR1 mutations in cell-free DNA linked with worse outcomes in metastatic breast cancer Comment by Reshma L Mahtani, DO I t is becoming increasingly clear

Prevalence of ESR1 mutations in cell-free DNA and outcomes inmetastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial JAMA Oncology Take-home message • The authors analysed cell-free DNA from a previous phase 3 study that included 724 women with metastatic ER-positive breast cancer to deter- mine the prevalence of mutations in estrogen receptor α (ESR1) and to determine whether these mutations are associated with inferior outcomes. Of 541 evaluable patients, 156 (28.8%) had ESR1 mutations. Mutations in ESR1 were associated with significantly worse overall survival compared with wild-type mutations (OS, 32.1 v 25.99 v 19.98 months for wild-type, D538G, and Y537S mutations, respectively). • In patients with ER-positive breast cancer treated with aromatase inhibi- tors, ESR1 mutations are prevalent, with increased disease aggressiveness associated with Y537S and D538G mutations. Abstract IMPORTANCE Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mu- tations and their potential impact on clinical outcomes has not been established. OBJECTIVE To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is as- sociated with inferior outcomes. DESIGN, SETTING, AND PARTICIPANTS From December 16, 2014, to August 26, 2015, we analysed cell-free DNA (cfDNA) from baseline plasma samples from partici- pants in the BOLERO-2 double-blind phase 3 study that randomised patients from 189 centres in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm. INTERVENTIONS Patients were randomised to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo. MAIN OUTCOMES AND MEASURES The 2 most frequent mutations in ESR1 (Y537S and D538G) were analysed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival. RESULTS Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09–36.40 months]; D538G, 25.99 months [95% CI, 19.19–32.36 months]; Y537S, 19.98 months [13.01–29.31 months]; both mutations, 15.15 months [95% CI, 10.87–27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02–0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane. CONCLUSIONS AND RELEVANCE ESR1 mutations are prevalent in ER-positive aro- matase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology. JAMA Oncol 2016 Aug 11;[Epub ahead of print], Chandarlapaty S, Chen D, He W, et al.

mutation, but not in those with the Y537S mutation or with both muta- tions. As they point out, the small number of Y537S mutations in each arm could certainly be contributory. This highlights the need for addi- tional analyses to further clarify the benefit of various targeted therapies in the presence of ESR1 mutations. Ultimately, this information will be useful to determine appropriate sequencing of therapies.

inhibitors) to overcome hormonal re- sistance, it will become important to identify the benefit of these agents in the presence of ESR1 mutations. A previously reported analysis of the PALOMA-3 trial indicated that palbociclib was highly efficacious regardless of ESR1 mutation status. In this article, the authors report an improvement in PFS with the ad- dition of everolimus in wild-type pa- tients and in those with the D538G

that ESR1 mutations are related to AI resistance in ER+ meta- static breast cancer and are acquired mutations. These data are consistent with previously reported data indi- cating that circulating ESR1 muta- tions are an independent prognostic factor for overall survival. In the era of the addition of targeted therapies to hormonal therapy (with agents such as CDK inhibitors and mTOR

Comment by Lee S Schwartzberg, MD, FACP R ecent evidence has identified mutations in the oestrogen re- ceptor alpha, or ESR1, gene as one of the major causes of resistance to endocrine therapy in ER+ breast cancer. However, many of the samples tested to date were from small series, and outcome data were variable.

This study adds strength to the concept that acquired mutations in ESR1 are responsible for endocrine resistance in a significant number of patients in the large ER+ metastatic breast cancer population.

This large retrospective analysis of the BOLERO-2 trial, testing the addition of everolimus to AI therapy, represents the largest set of patients from a prospective clinical trial with PFS and OS outcomes known. The investigators tested for ESR1 muta- tions by using cell-free DNA and specifically focusing on only two common activating mutations; so, the study by no means represents the spectrum of potentially func- tional ESR mutations discoverable with other technologies such as whole exome sequencing.

small to do anything except suggest further exploration into the predictive value of having an ESR1 mutation. This study adds strength to the concept that acquired mutations in ESR1 are responsible for endocrine resistance in a significant number of patients in the large ER+ metastatic breast cancer population. Moreover, these alterations are easy to detect in blood, opening a whole new area of research, and the findings are poten- tially even clinically actionable now.

Nonetheless, they found that almost one-third of patients with blood samples from the beginning of the study had a mutation in the gene, with more occurring in those previously exposed to an AI in the metastatic setting than those in the adjuvant setting. Having one of the two mutations was prognostic, as- sociated with worse outcome both in PFS and OS. The addition of everolimus seemed to impact the mutational patients differently by mutation, but the numbers were too

Relationship between age and breast cancer survival is subtype-dependent Comment by Lee S Schwartzberg, MD, FACP Y oung age (<40 years) is associated with worse outcome than mid- dle age in women with breast cancer. In part, this has been due to a higher likelihood of triple-negative breast cancer in younger

Subtype-dependent relationship between young age at diagnosis and breast cancer survival Journal of Clinical Oncology Take-home message

cancer-specific survival. RESULTS A total of 17,575 women with stage I to III breast cancer were eligible for analysis, among whom 1,916 were ≤ 40 years of age at diagnosis. Median follow- up time was 6.4 years. In a multivariable Cox proportional hazards model control- ling for sociodemographic, disease, and treatment characteristics, women ≤ 40 years of age at diagnosis had greater breast cancer mortality (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.7). In stratified analyses, age ≤ 40 years was associated with statis- tically significant increases in risk of breast cancer death among women with luminal A (HR, 2.1; 95% CI, 1.4 to 3.2) and luminal B (HR 1.4; 95% CI, 1.1 to 1.9) tumours, with borderline significance among women with triple-negative tumours (HR, 1.4; 95% CI, 1.0 to 1.8) but not among those with human epidermal growth factor receptor 2 subtypes (HR, 1.2; 95% CI, 0.8 to 1.9). In an additional model controlling for detec- tion method, young age was associated with significantly increased risk of breast cancer death only among women with luminal A tumours. CONCLUSION The effect of age on survival of women with early breast cancer seems to vary by breast cancer subtype. Young age seems to be particularly prognostic in women with luminal breast cancers. J Clin Oncol 2016 Aug 01;[Epub ahead of print], Partridge AH, Hughes ME, Warner ET, et al.

• The effect of age on breast cancer-specific survival was analysed in a multi- center study of 17,575 women with newly diagnosed stage I to III breast can- cer. Median follow-up was 6.4 years. After controlling for sociodemographic, disease, and treatment characteristics, breast cancer mortality was found to be greater in women ≤40 years of age (n = 1916) at diagnosis. Among women with luminal A and luminal B tumours, but not those with an HER2 subtype, young age was associated with significant increases in risk of breast cancer-associated death. Further analysis that controlled for detection method revealed the association of young age with increased risk of death was only among women with luminal A tumours. • The relationship between survival and age at diagnosis for women with early breast cancer is dependent on breast cancer subtype. Abstract

women. In this interesting study of the NCCN database, it appears that younger women with luminal A mo- lecular subtype of breast cancer (ER/ PR+, HER2−, low proliferation) did worse compared with those with other subtypes when multiple potential vari- ables are accounted for in a multivariate analysis. These results, while a bit sur- prising, are consistent with the TEXT/ SOFT prospective data, which showed that young women with ER+ breast can- cer had a markedly worse outcome than older but still premenopausal women. It also suggests that increased endocrine therapy may be the best way to reduce mortality in young women.

PURPOSE Youngwomen are at increased risk for developing more aggressive subtypes of breast cancer. Although pre- vious studies have shown a higher risk of breast cancer recurrence and death among young women with early-stage breast cancer, they have not adequately addressed the role of tumour subtype in outcomes. METHODS We examined data from women with newly diagnosed stage I to III breast cancer presenting to one of eight National Comprehensive Cancer Network centres between January 2000 and December 2007. Multivariable Cox proportional haz- ards models were used to assess the relationship between age and breast

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