PracticeUpdate: Haematology & Oncology

VOL. 2 • NO. 2 • 2017

RESEARCH NEWS AND VIEWS FROM ELSEVIER

ISSN 2206-463X

Identifying key molecular alterations in prostate cancer

OPINION

... in the triplet combination, cetuximab likely serves to counteract feedback-loop activation of EGFR after BRAF blockade. It will remain to be seen if regulatory agencies, guideline committees will see the results as practice-changing  19 EDITOR’S PICKS Longer-interval dosing of zoledronic acid effective in patients with bone metastases 7 8 Small renal mass biopsy avoids unnecessary surgery mpMRI for diagnosing prostate cancer recurrence superior to PET, CT ECCO 2017

It is imperative to unravel prostate cancer biology to enable the identification of key molecular events and molecules that aid in diagnosis, prognosis, and the discovery of new therapeutic targets. 3

ASCOGI 2017

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Simultaneous EGFR, BRAF inhibition effective in BRAF V600-mutated mCRC

More patients with rectal cancer are candidates for a watch-and- wait approach

Improved survival benefit with increased docetaxel cycles in prostate cancer JAMA Oncology The study results indicate that continuing docetaxel chemotherapy improves clinical benefit in patients with mCPRC, but further prospective studies are needed to validate these findings.

First-line ceritinib vs platinum-based chemotherapy in advanced ALK- rearranged non-small cell lung cancer The Lancet Ceritinib was associated with a significant improvement compared with chemotherapy as a first-line treatment in patients with ALK- rearranged NSCLC.

Vemurafenib in metastatic melanoma patients with brain metastases Annals of Oncology The results showed that melanoma BM responded in a clinically meaningful way to vemurafenib. This agent can be administered without causing significant CNS toxicity.

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I have high grade serous ovarian cancer TEST ME

for BRCAm If I am positive

TREAT ME

with Lynparza TM *

*as maintenance therapy for PSR disease, in response after platinum-based chemotherapy (must have ≥ 2 courses) 1

NOW PBS LISTED 2

FROM 1 ST FEBRUARY 2017

PBS Information: Lynparza. Authority Required. For maintenance treatment of germline BRCA mutated platinum-sensitive relapsed high-grade serous ovarian, fallopian tube or primary peritoneal cancer for patients who have responded to prior platinum based chemotherapy. Refer to PBS schedule for full authority information.

Explanatory note: Patients who are found to have a germline BRCA1 or BRCA2 mutation should be referred for post-test genetic counselling, as there may be implications for other family members. Appropriate genetic counselling should be provided to the patient either by the specialist treating practitioner, a genetic counselling service or a clinical geneticist on referral.

MBS item 73295: Detection of germline BRCA1 or BRCA2 gene mutations, in a patient with platinum-sensitive relapsed ovarian, fallopian tube or primary peritoneal cancer with high grade serous features or a high grade serous component, and who has responded to subsequent platinum-based chemotherapy, requested by a specialist or consultant physician, to determine whether the eligibility criteria for olaparib under the Pharmaceutical Benefits Scheme (PBS) are fulfilled.

BEFORE PRESCRIBING, PLEASE REVIEW FULL PRODUCT INFORMATION AVAILABLE ON REQUEST FROM ASTRAZENECA ON 1800 805 342 OR www.astrazeneca.com.au/PI LYNPARZA ® (olaparib) Minimum Product Information: INDICATIONS: Monotherapy for the maintenance treatment of patients with platinum - sensitive relapsed BRCA - mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) after platinum - based chemotherapy. Prior treatment must have included at least 2 courses of platinum - based regimens. CONTRAINDICATIONS: Hypersensitivity to the active substance (olaparib) or to any of the excipients. PRECAUTIONS: Haematological toxicity is common in patients treated with olaparib and usually mild - moderate. Patients should not start treatment with LYNPARZA until they have recovered from haematological toxicity caused by previous anti - cancer therapy. A baseline complete blood count followed by monthly monitoring is recommended for the first 12 months of treatment and periodically after this. Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in a small number of patients (<1%) and the majority of reports have been fatal. Pneumonitis has been reported in a small number of patients receiving olaparib, and some reports have been fatal. Use in pregnancy: Category D. LYNPARZA may cause foetal harm when administered to a pregnant woman. Women of child bearing potential must use effective contraception during treatment and for 1 month after receiving the last dose. Use during lactation: Breast feeding should be avoided in women receiving LYNPARZA and for 1 month after the last dose. Use in Men: Not indicated Children or adolescents: Not indicated. Interactions with other medicines. INTERACTIONS: LYNPARZA co administration with strong CYP3A inducers or inhibitors should be avoided. Addition of LYNPARZA and cytotoxic agents has been shown to potentiate and prolong myelosuppressive side effects. ADVERSE REACTIONS : Very common (≥10%): decreased appetite, headache, dysgeusia, dizziness, nausea, vomiting, diarrhoea, dyspepsia, fatigue, anaemia, neutropenia, lymphopenia, mean corpuscular volume elevation, increased creatinine; Common (≥1% to <10%): stomatitis, upper abdominal pain, thromboyctopenia; for other listed adverse reactions, see full PI. DOSAGE AND ADMINISTRATION: 400 mg (eight 50 mg capsules) taken twice daily, equivalent to a total daily dose of 800 mg. LYNPARZA should be taken on an empty stomach and patients should refrain from eating for 2 hours. Date of first inclusion in the ARTG: 7th January 2016. References 1. Lynparza Approved Product Information 10 October 2016. 2. PBS Website http://www.pbs.gov.au/pbs/home [Accessed 1 February, 2017]. Lynparza TM is a trademark of the AstraZeneca group of companies. AstraZeneca Pty. Ltd. ABN 54 009 682 311. 66 Talavera Road, Macquarie Park, NSW 2113. AstraZeneca Medical Information: 1800 805 342. www.astrazeneca.com.au. AU-1960, WL294703, January 2017.

NEWS 3

Identifying key molecular alterations in prostate cancer may help in diagnosis and prognosis M etabolic and proteomic alterations can be identified in biopsy specimens from patients with prostate cancer that enable

PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practi- tioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Lee Schwartzberg MD FACP Associate Editors Isabel Cunningham MD Axel Grothey, MD Advisory Board Kimberly Blackwell MD, Roxana Dronca MD, Andre Goy MD, Annette Hasenburg Prof Dr med, David Henry MD, Eric Jonasch MD, Jeffrey Kirshner MD, FACP, Ruben Niesvizky MD, Howard Scher MD, Roger Stupp, MD Editorial Contributors Brandt Esplin MD PhD, EDITORIAL AUSTRALIA Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Jeremy Jones MD, Jarushka Naidoo MD, Moshe Ornstein MD, Erin Schenk MD PhD PracticeUpdate.com is your online resource for in- depth insights and inside commentary that matter most to medical specialists. PracticeUpdate Haematology &Oncology brings you highlights of key local and international conferences, relevant and timely medical news, expert opinions and journal article reviews in a convenient print periodical. Content is guided by PracticeUpdate’s world-renowned editorial and advisory board members who represent community practitioners and academic specialists with cross-disciplinary expertise. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia 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. Becauseofrapidadvances in themedicalsciences, in particular, independent verification of diagnoses and drug dosages should bemade. 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. ISSN 2206-463X (Print) ISSN 2206-4648 (Online) ADVERTISING Fleur Gill fleur.gill@elsevier.com 02 9422 8572 Linnea Mitchell-Taverner l.mitchell@elsevier.com 02 9422 8587

the distinction between benign and malignant tissue, conclude results of a spectroscopy and microarray study. Margarita Fardilha, MD, of the University of Aveiro, Portugal, explained that prostate cancer remains a major health problem worldwide. Treat- ment is still a challenge for urologists, as well as the establishment of a clear prognosis. Prognosis is compromised by the lack of sensi- tivity and specificity of available markers. It is imperative to unravel prostate cancer biology to enable the identification of key molecular events and molecules that aid in diagnosis, prognosis, and the discovery of new therapeutic targets. Dr Fardilha and colleagues set out to identify metabolic and proteomic alterations that ena- ble the distinction between prostate benign and malignant tissue. Biopsies from prostate tumours and adjacent benign tissue from the central zone of the gland were obtained from eight patients. Prostate-specific antigen blood levels, prostate carcinoma stage (TNM), and Gleason score were determined in all patients. Each sample was divided and analysed using two approaches: infrared spectroscopy, anti- body microarray. These approaches allowed for analysis of the expression and phosphorylation state of 800 signalling proteins. The list of differentially expressed/regulated proteins between normal and tumour conditions was then subjected to an extensive bioinformatics analysis to inte- grate and complement all data with existing studies. Principal component analysis of spectroscopic signals derived from prostate cancer biopsies and adjacent benign tissues revealed different spectra for each condition. Dysregulations in lipid metabolism, lower amounts of polysaccharides and glycogen, as well as increased content of nucleic acids and protein phosphorylation were the most relevant alterations observed in prostate cancer tissues. Moreover, 40 proteins were identified as differ- entially expressed between the two conditions. Thirteen proteins revealed alterations in their phosphorylation levels. Identification of known prostate cancer-related

© ECCO2017 European Cancer Congress

proteins reinforced the fidelity of the screen. Analysis of protein–protein interaction networks and ontologies showed disruption of cell signalling events during prostate carcinogenesis. Dr Fardilha concluded that metabolomics and proteomic approaches can provide vast informa- tion about carcinogenic processes. Integration of different “omic” approaches are increasingly important when moving to the era of person- alised medicine. This transition requires the understanding of disease as an entire, integrated pathophysiological process Dr Fardilha and coinvestigators showed that applying two distinct approaches to the same set of samples enables retrieval of a substantial amount of complementary information. Using these approaches not only increases the understanding of prostate carcinogenesis, but also allows for identification of key molecular alterations that may aid in accurate diagnosis/ prognosis and in the development of new, targeted therapies.

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More from European Cancer Congress 2017 on page 8

VOL. 2 • NO. 2 • 2017

10 top advances in diagnostic and molecular pathology in breast cancer NEWS 4

O ver the last 2 decades there has been great advancement in the field of breast cancer molec- ular classification and prognostication, and in the understanding of the pathogenesis of this heterogeneous disease. Applications of high throughput molecular techniques coupled with state-of-the art bioinformatics approaches have generated vast amounts of data and opened avenues to refine breast cancer classification and identify novel therapeutic targets with a subse- quent move towards personalised therapy. Here are our 10 hot topics to watch.

Leading pathologists, Jane E. Dahlstrom*, Emad A.Rakha # , Sunil R. Lakhani†, Stuart J. Schnitt‡ and colleagues share their current ‘hot topics’ in the field of breast diagnostic and molecular pathology and the research to watch.

1 . Application of molecular techniques Rakha and Green 1 provide an update on the appli- cation of molecular techniques with regard to breast cancer diagnosis, prognosis and outcome prediction. They briefly highlight current contri- butions of this emerging technology towards our understanding of breast cancer, in addition to the essential role of immunohistochemistry and other molecular techniques in the diagnosis and differ- ential diagnosis of breast lesions. 2 . Molecular profiling Ross and Gay 2 present a review on the molecular profiling of advanced breast cancer and the role of comprehensive genomic sequencing technology. They discuss massive parallel sequencing and next generation sequencing (NGS) technology and its potential applications in breast cancer research and management, in particular identification of targetable, clinically relevant genomic alterations. 3 . Stromal-epithelial interactions McCuaig and colleagues 3 discuss the biological and clinical significance of stromal-epithelial interactions in breast cancer. In this review recent advances in our understanding of how cancer epithelial cells interact with their microenvironment and how this knowledge can be exploited clinically are presented. 4 . DNA damage Three main pathways play a major role in DNA repair in breast cancer. This article highlights how basic science can be translated into clinical bene- fit. For example, there is evidence to indicate the efficacy of targeting DNA damage repair mole- cules in BRCA-mutated breast cancer using PARP inhibitors. In contrast, the response to such therapy is lim- ited in sporadic cases, despite the presence of evidence of DNA repair defect suggesting differ- ent mechanisms other than BRCA gene mutation. The different mechanisms of DNA repair in breast cancer and the concept of synthetic lethality,

BRCAness and the therapeutic potential of some proteins involved in DNA repair are highlighted in the article by Ali et al. 4 5 . Ki67 use There is a continuous effort to identify new prog- nostic and predictive markers; however, there is also a need to refine, validate and further assess the clinical utility of existing variables. Although the prognostic value of Ki67 in breast cancer is well demonstrated and some authors have pro- vided evidence for its predictive value, at least in certain situations, its application in routine prac- tice remains less than what was initially expected. The issue of reproducibility of Ki67 staining and scoring, and the use of several cut-off points have resulted in a delay in its application in routine practice and some current international guidelines have recommended not to use Ki67 to guide treat- ment decisions. This topic and other issues related to Ki67 use in breast cancer are covered in the article by Penault-Llorca and Radosevic-Robin. 5 6 . Tumour infiltrating lymphocytes A topic which has gained a lot of attention fol- lowing a series of publications demonstrating its prognostic value and the emerging role of immuno- therapy is tumour infiltrating lymphocytes (TILs). Luen et al 6 provide a comprehensive review on TILs and the emerging role of immunotherapy in breast cancer. Although breast cancer has not previously been considered a highly immunogenic cancer, retrospective analysis of clinical trial sam- ples has demonstrated the potential role of host immunosurveillance in influencing the biology of at least certain subtypes of breast cancer; namely triple negative and HER2-positive classes. Evi- dence indicates that TILs are associated with improved pathological complete response and patient outcome. In their article they cover the existing methodologies of assessment of TILs in breast cancer and efforts to standardise TILs eval- uation, and discuss clinical relevance of TILs and ways to improve efficacy of immunotherapeutic approaches in breast cancer.

* ACT Pathology, The Canberra Hospital and ANU Medical School, Canberra, Australia; # Department of Cellular Pathology, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom; † Breast Pathology Group, The University of Queensland Centre for Clinical Research, Discipline of Molecular & Cellular Pathology, The University of Queensland School of Medicine and Pathology Queensland, Brisbane, Australia; ‡ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

NEWS 5

7 . Role of mathematical modelling A novel subject that reflects the benefit of integration of pathology, molecular biology and mathematics is in Simmons et al 7 , which reviews the role of mathematical modelling and simulation in deciphering breast cancer heterogeneity and underlying biophysical processes. Different models are elucidated including equation-based models, agent-based modelling, multi-scale modelling, lattice-based models and image-driven modelling. Novel aspects of breast cancer dynamics and perspectives on the role of mathematical modelling in understanding breast cancer development, invasion and treatment therapies are presented. 8 . Diagnosing salivary gland-like tumours Salivary gland-like tumours are rare breast lesions characterised by epi- thelial and myoepithelial differentiation and they mimic salivary gland tumours. The morphology and immunoprofile of these lesions are widely variable and overlapping and these, in addition to their rarity, make their diagnosis in routine practice a challenging task. Prior knowledge of their classification, morphologic and immunophenotypic features is essential for the correct diagnosis, and knowledge of their clinical behaviour is essential in guidingmanagement decisions. Foschini and colleagues 8 in their article have provided a comprehensive overview of salivary gland-like tumours. 9 . Diagnosing vascular proliferations Vascular lesions are another area of diagnostic challenge. Although rare, different types of vascular lesions develop in the breast and it is not uncommon to find difficulty in distinguishing benign/atypical from malignant vascular entities despite the fundamental difference in the clinical behaviour andmanagement of the two. The commonplace use of local radiotherapy is associated with an increased risk of atypical/malig- nant vascular lesions, and specialist breast pathologists often face the dilemma of over- or underdiagnosis of low grade angiosarcoma on a core biopsy in addition to dealing with angiosarcoma in excision specimens. Ginter and colleagues 9 discuss the clinicopathological features of the most commonly encountered mammary vascular proliferations with some insight into differential diagnoses and ancillary studies that can be used to provide the most accurate diagnosis. Knowledge of diagnos- tic pitfalls in breast pathology can improve the accuracy of reporting and avoid unnecessary consequences.

10 . Mimics of malignancy Torous and colleagues 10 in their review address some benign entities that may be misinterpreted as malignant lesions (mimics of malignancy) and describe the salient features of these entities in an attempt to improve the awareness of such challenging lesions. Mucocele-like lesions, collagenous spherulosis,tubular adenosis, granular cell tumour, myofibroblastoma, Toker cells, lymph node epithelial inclusion and breast epithelial displacement following biopsy procedures are discussed in details with differential diagnosis, immunoprofile and management.

These Top 10 topics on breast cancer pathology are available collectively in a special issue of Pathology ( Pathology 2017; 49). Also available at www.sciencedirect.com/science/journal/00313025

References 1. Rakha EA, Green AR. Pathology 2017;49:111–9. 2. Ross JS, Gay LM. Pathology 2017;49:120–32.

3. McCuaig R, Wu F, Dunn J, et al. Pathology 2017;49:133–40. 4. Ali R, Rakha EA, Madhusudan S, et al. Pathology 2017;49:156–65. 5. Penault-Llorca F, Radosevic-Robin N. Pathology 2017;49:166–71. 6. Luen SJ, Savas P, Fox SB, et al. Pathology 2017;49:141–55. 7. Simmons A, Burrage PM, Nicolau Jr DV, et al. Pathology 2017;49:172–80. 8. Foschini MP, Morandi L, Asioli S, et al. Pathology 2017;49:215–27. 9. Ginter PS, McIntire PJ, Shin SJ. Pathology 2017;49:197–214. 10. Torous VF, Schnitt SJ, Collins LC. Pathology 2017;49:181–96.

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Discover more about rare haematology Visit our new resource centre rarehaematology.elsevierresource.com Bringing you relevant content: • Expert opinion • Journal articles – full text available to download • Current research • Conference coverage including ASH and EHA

The Rare Haematology Resource Centre is funded by Sanofi Genzyme and developed by Elsevier. Sanofi Genzyme has no editorial control over the content of the Resource Centre. All content therein has been subject to an independent editorial review.

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EDITOR’S PICKS 6

Higher rates of long-term overall survival with radiation and antiandrogen therapy for recurrent prostate cancer

Homayoun (Homi) Zargar, MD, FRACS 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, University of Melbourne.

Rajesh Nair, FRCS (Urol), FEBU, MSc is a UK-trained urological surgeon undergoing advanced fellowship training in robotics and uro- oncology at the Royal Melbourne Hospital.

T raditional standard of care for patients who exhibit biochemical recurrence (elevated and rising prostate-spe- cific antigen [PSA] level) and therefore recurrent prostate cancer following radical prostatectomy is salvage radiotherapy. Shi- pley and colleagues evaluate the impact of adding an antiandrogen on disease-specific and overall survival. This double-blind pla- cebo controlled study assessed 760 men who had undergone radical prostatectomy with pelvic lymphadenectomy with patho- logical T-stage, T2 or T3 and N0 prostate adenocarcinoma. All patients demonstrated evidence of biochemical recurrence as defined by a PSA of 0.2–4.0 ng/mL and were randomised to salvage radiation

a number of caveats one must consider when evaluating the data presented. Most concomitant androgen deprivation regi- mens focus on using a luteinising hormone releasing hormone analogue. Certainly, most comparative ongoing salvage radiation trials use this and not bicalutamide, which here is delivered at the 150 mg once daily. This is far higher than the recommended dosage of 50 mg once daily. In addition, the timing of adjuvant radiation in this cohort of trial patients appears to be significantly delayed when compared to the current standard, which is when PSA reaches 0.2–0.5 ng/dL. Certainly, this patient cohort is an impor- tant one for urologists and oncologists alike. While this study certainly is informative, we

therapy alone or in combination with bical- utamide monotherapy (150 mg/day) for 2 years. With a median follow-up of 13 years, over- all survival at 12 years was 76.3% in the bicalutamide group vs 71.3% in the pla- cebo group. Death from prostate cancer was 5.8% vs 13.4% in the bicalutamide and pla- cebo groups, respectively. Finally incidence of metastatic disease at 12 years was 14.5% and 23% in the bicalutamide and metastatic disease groups, respectively. This study is unique in demonstrating the addition of antiandrogen therapy to sal- vage radiation therapy reduced overall and cancer-specific survival, and progression to metastatic disease. However, there are

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275) T raditional treatment for metastatic bladder cancer is cisplatin-based chemotherapy. Unfortunately, due patients are ineligible to receive this treat- ment. Their prognosis is poor. found on tumour cells binding to PD-1 on immune cells suppressing the host immune response.

Nivolumab, is a humanised IgG4 PD-1 immune checkpoint inhibitor. This form of immunotherapy targets the protein PD-L1

to comorbidities, deteriorating renal func- tion or cardiac impairment, over 60% of

Sharma et al report the promising results of a multicentre, phase II, single-arm study examining nivolumab in patients with metastatic or locally advanced urothelial carcinoma, whose disease progressed or recurred despite previous platinum-based chemotherapy. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression, clinical deteriora- tion or as a result of toxicity. Of the 265 patients evaluated, median follow-up was 7 months, with an overall objective response rate of 19.6%. Interestingly, this study goes one step further. PD-L1 expression was recorded from tissue obtained (>5% and 1%). Of those who expressed >5% and >1% PD-L1 expression, response to nivoul- mab was 28.4% and 23.8%, respectively.

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial Lancet Oncol 2017 Jan 25;[EPub Ahead of Print], P Sharma, M Retz, A Siefker-Radtke, et al Take-home message • In this single-arm study, 265 patients with metastatic or surgically unresectable advanced urothelial carcinoma were given nivolumab, a PD-1 inhibitor. A confirmed objective response was achieved in 28.4% (23/81), 23.8% (29/122), and 16.1% (23/143) of patients with PD-L1 expression ≥ 5%, ≥ 1%, and <1%, respectively. Overall survival was 7 months. • Nivolumab treatment has an acceptable safety profile and is clinically beneficial, but improved outcomes did not correlate with PD-L1 expression in patients with unresectable advanced urothelial carcinoma.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

EDITOR’S PICKS 7

ARTICLE OF THEMONTH Longer-interval dosing of zoledronic acid effective in patients with bone metastases Introducing Editor’s Picks, a new section featuring the most recent top clinical trials in oncology and haematology specially selected by the PracticeUpdate Oncology Editorial and Advisory Board members. T he use of zoledronic acid in patients with metastatic breast cancer (MBC) with bony metastases is crucial to prevent skeletal-related events, which have been shown to occur in up to 50% of patients when untreated. Skeletal-related events are defined as fractures, spinal cord compression, need for surgery or radiation to relieve symptomatic disease, and hypercalcemia of malignancy. Bone metastases disrupt the normal homeostasis between bone formation and resorption by promoting osteoclast maturation and activity and increased bone resorption. Bone is a common site of recurrence in breast cancer. Bony metastases significantly impact quality of life; therefore, MBC patients should be offered bisphosphonate (or RANK ligand inhibitor) therapy at diagnosis with bone metastases. However, these therapies are not without potential side effects. A rare and serious complication is oste- onecrosis of the jaw. Therapies are also associated with the need for monthly visits to the infusion suite, which can be disruptive especially to a patient who would otherwise not require these visits as she is not on chemotherapy. The option to dose zoledronic acid less frequently without compromising efficacy is therefore an attractive alternative for patients. JAMA 2017;317(1):48-58. AL Himelstein, JC Foster, JL Khatcheressian, et al. Impact on metastatic breast cancer By Reshma L. Mahtani DO

Radiation with or without antian- drogen therapy in recurrent prostate cancer N Engl J Med 2017;376:417-428, Shipley WU, Seif- erheld W, Lukka HR, et al, for the NRG Oncology RTOG. Take-home message • In this double-blind, placebo-controlled trial involving 760 patients who had undergone primary prostatectomy with a lymphadenectomy and had disease with a tumour stage T2 or T3, no nodal involvement, and a detectable PSA level of 0.2–4.0 ng/mL, overall survival at 12 years was 76.3% in the bicalutamide group vs 71.3% in the placebo group; death from prostate cancer was 5.8% vs 13.4% in the bicalutamide and placebo groups, respectively. • The addition of 24months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo.

also await the results of the RADICALs and GETUG-16 (salvage radiation trials) to assess if practice should change.

For patients who expressed <1% of PD-L1, response was 16.1%. Grade 3–4 treatment-re- lated adverse events occurred in 18%, with three treatment-related deaths. This is a novel study; once again it mirrors response rates observed in previous studies involving checkpoint inhibitors. Of particu- lar interest, monotherapy with nivolumab is beneficial regardless of whether PD-L1 is expressed. However, perhaps most excitingly, it heralds an era where individualised therapy in bladder cancer can be based on molecular marker expression. Much like oestrogen and Herceptin receptor expression can influence treatment paradigms in breast cancer, personal- ised care is a reality for bladder cancer. Patients can be directly counselled regarding potential response rates and therapeutic strategies based on PD-L1 expression. It remains to be seen whether routine, efficient and cost-effective PD-L1 expression is clinically applicable.

Dr Mahtani is a haematologist/medical oncologist and Assistant Clinical Professor of haematology/oncology at the Sylvester Comprehensive Cancer Center, Miami.

Take-home message • This was a randomised, open-label phase III trial designed to assess whether 12-week dosing of zoledronic acid was noninferior to every 4-week dosing in 1822 patients with bone metastatic breast cancer, prostate cancer, and multiple myeloma. There was no significant difference between the rate of skeletal-related events among patients who received zoledronate every 12 weeks and those who received it every 4 weeks. • The authors concluded that longer-interval treatment with zoledronic acid may be an acceptable treatment modality among patients with bone metastases.

VOL. 2 • NO. 2 • 2017

CONFERENCE COVERAGE 8

European Cancer Congress 2017

27–30 JANUARY 2017 | AMSTERDAM, THE NETHERLANDS

ECCO2017 brings together Europe’s oncology professionals in a multidisciplinary forum to progressively think on cancer policy, training and education, cancer research, prevention, diagnosis and treatment of cancer patients. This year’s meeting touched on various topics including identifying key molecular events, use of biopsy in small renal masses, multiparametric MRI being superior to PET and CT, and the outcomes of phase1b KEYNOTE-012 trial.

Biopsies of small renal masses help avoid unnecessary surgery B iopsy of small renal masses is a way to reduce overtreatment, cost, and most important, treatment-related mor- bidity, concludes results of a retrospective, single-centre study. Dr McPhee and colleagues proposed to val- idate the safety, accuracy, and reliability of renal biopsy in their centre. They also eval- uated the use of biopsies to guide treatment decisions.

Recent series from Richard et al in Toronto have shown concordance rates of 90%. Dr McPhee’s series showed a 100% concord- ance rate of biopsy with surgical histology. Grading of renal biopsy was not routinely reported, so whether this level of concord- ance would apply to tumour grading could not be confirmed. Dr McPhee concluded that the study provides further evidence of the benefit of renal biopsy. With the increasing use of imaging, an increasing number of small renal masses are being diagnosed. The majority of small renal masses are still treated with upfront definitive treatment, which results in overtreatment. Consequently, in patients in whom definitive treatment is being considered, biopsy of small renal masses can reduce overtreatment, cost, and most important, treatment-related morbidity.

Arthur McPhee, MD, of Glasgow Royal Infirmary, UK, explained that the incidence of small renal masses has been rising over the past decade, in keeping with the global increasing incidence in renal cell carcinoma seen over past decades. Studies have shown that 20–30% of small renal masses are benign, yet are unable to reliably distinguish between benign and malignant disease radiologically. Renal biopsy has been established as safe and reliable for obtaining information on the pretreatment histology of renal masses. Adoption by the urological community as a standard approach to guiding treatment, how- ever, remains low, as available evidence was in high-volume centres.

Patients who underwent biopsy of small renal masses between 2013 and 2016 were identified using a prospectively maintained electronic patient record system and a pathol- ogy database. Diagnostic and concordance rates were presented as proportions. A total of 208 biopsied small renal masses were included in the analysis and comparison with other high-volume centres. Of biopsied masses, the initial biopsy was diagnostic in 88% (n=184) of cases, of which 16.43 (n=34) were found to be benign. Only one patient experienced an adverse event (0.5%) and required a blood transfusion for postbiopsy bleeding. Concordance rates have improved over time.

PracticeUpdate Editorial Team

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ECCO2017 9

Cabozantinib proves superior to everolimus in advanced renal cell carcinoma with bonemetastases R esults of the phase III METEOR trial of cabozantinib vs everolimus in advanced renal cell carcinoma have demonstrated that cabozantinib is superior to everolimus. Toni Choueiri, MD, of Dana-Farber Cancer Institute, Boston, Massachusetts, explained that bone metastases are associated with poor outcomes in patients with metastatic renal cell carcinoma. METEOR evaluated the efficacy and safety of cabo- zantinib vs everolimus in patients with previously treated advanced renal cell carcinoma. Overall survival was significantly prolonged with cabozantinib with a median overall survival of 21.4 vs 16.5 months with everolimus (hazard ratio 0.66, 95% CI 0.53–0.83, P = 0.0003). Progression-free survival and objective response rate were also significantly improved with cabozantinib vs everolimus [HR for progression-free survival 0.51 (95% CI 0.42– 0.62, P < 0.0001). Cabozantinib showed activity in bone metastases in preclinical and clinical studies performed in 2014. Dr Choueiri reported outcomes in patients enrolled in METEOR with bone metastases. A total of 658 patients were stratified by Memorial Sloan Kettering Cancer Center risk group and number of prior vascular endothelial growth factor receptor tyrosine kinase inhibitors and randomised 1:1 to cabozantinib (60 mg qd) or everolimus (10 mg qd). Clinical outcomes included progression-free survival, objective response rate, overall survival, and safety. Exploratory endpoints were bone scan response per independ- ent radiology committee in patients with bone scan lesions at baseline, incidence of skeletal-related events, and changes in bone turnover markers. At baseline, 142 patients harboured bone metastases and 112, visceral metastases as well. Patients with bone metastases were distributed in Memorial Sloan Kettering Can- cer Center risk group consistently with the overall study population. Hazard ratios for progression-free survival with cabozantinib vs everolimus were 0.33 (95% CI 0.21–0.51) in patients with bone and 0.26 (95% CI 0.16–0.43) for patients with bone and visceral metastases. Overall survival was also markedly improved, with hazard ratios of 0.54 (95% CI 0.34–0.84) in patients with bone metastases (median overall survival 20.1 months for cabozantinib vs 12.1 months for everolimus) and 0.45 (95% CI 0.28–0.72) in patients with bone and visceral metastases (median overall survival was 20.1 months with cabo- zantinib vs 10.7 months with everolimus). The objective response rate per independent radiology committee with cabozantinib was 17% for patients with bone metastases and 20% for those with bone and visceral metastases. Bone scan response per independent radiology committee was 18% with cabozantinib vs 10% with everolimus. At least one skeletal-related event occurred in 12% (cabo- zantinib) and 14% (everolimus) of patients, in four cabozantinib and eight everolimus cases of spinal cord compression. For patients with a history of skeletal-related events at randomisation, the incidence of postrandomisation skeletal-related events was 16% (cabozantinib) and 34% (everolimus) and included 0 (cabozantinib) and five (everolimus) cases of spinal cord compression. Reductions in bone markers P1NP and CTx were greater with cabozantinib than with everolimus. The most common adverse events in patients with bone metastases were consistent with those observed in the overall study population. Dr Choueiri concluded that progression-free and overall survival, as well as the objec- tive response rate, in patients with bone metastases were improved with cabozantinib vs everolimus and consistent with results for the overall population. Outcomes in bone metastasis-related endpoints supported the observed superior efficacy of cabozantinib vs everolimus in METEOR.

When diagnosing local recurrence of prostate cancer in the early stages of recurrence, multiparametric MRI is superior to PET and CT scanning. Patients who present with de novo metastatic breast cancer and harbour fewer than two sites of metastatic disease are more likely to achieve prolonged overall survival when treated

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with HER2 therapy in combination with chemotherapy.

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Preliminary results have shown that eribulin can potentially suppress the epithelial-mesenchymal transition... after eribulin treatment, epithelial makers were increased and mesenchymal markers decreased in two-thirds of tumours.

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PracticeUpdate Editorial Team

VOL. 2 • NO. 2 • 2017

GET MORE PEOPLE WITH CML-CP WHERE THEY NEED TO BE 1-3†

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

Please review approved Product Information before prescribing. Approved Product Information can be accessed at http://www.novartis.com.au/products_healthcare.html. Please note change(s) in Product Information. Indications: Treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (Ph+CML) in chronic phase. Treatment of chronic or accelerated phase Ph+CML in adult patients resistant to or intolerant of at least one prior therapy including imatinib. Dosage: Patients with newly diagnosed Ph+CML-CP: 300 mg twice daily; patients with CP and AP Ph+CML resistant to or intolerant of at least one prior therapy including imatinib: 400 mg twice daily. Monitoring of response to therapy in Ph+ CML should guide appropriate CML management. Doses should be taken about 12 hours apart without food. No food should be consumed for at least two hours before and one hour after the dose. For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. Not more than one teaspoon of applesauce and no food other than applesauce must be used. Contraindications: Hypersensitivity to nilotinib or excipients. Precautions: Thrombocytopenia, neutropenia and anaemia managed by temporary withdrawal or dose reduction; complete blood counts every two weeks for the first two months, monthly thereafter or as clinically indicated; patients at risk of QTc prolongation (e.g. patients with hypokalaemia, hypomagnesaemia, congenital long QT syndrome, with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia; patients taking anti-arrhythmic drugs or other drugs that may lead to QT prolongation); ECG is recommended prior to treatment, repeat after 7 days and as clinically indicated; correct hypokalaemia or hypomagnesaemia prior to treatment; uncommon cases (0.1 to 1%) of sudden death have been reported in patients with past medical history of cardiac disease or significant cardiac risk factors (not in the newly diagnosed Ph+ CML-CP study). Cardiovascular events were reported in 48 month extended follow-up trial in newly diagnosed CML patients and observed in the post-marketing reports. Grade 3/4 cases of cardiovascular events included peripheral arterial occlusive disease, ischemic heart disease and ischemic cerebrovascular events. If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The CV of patients should be evaluated and the CV risk factors should be monitored and actively managed during therapy according to standard guidelines. It is recommended that the lipid profiles be determined before initiating treatment with Tasigna, assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy. Blood glucose levels should be assessed prior to initiating Tasigna therapy and monitored during treatment. Test for hepatitis B infection before initiating treatment with Tasigna. In patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment, consult experts before initiating treatment. Closely monitor for signs and symptoms of active hepatitis B infection in carriers of hepatitis B virus throughout therapy and for several months following termination of therapy. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the etiology should be evaluated and patients treated accordingly. Comorbidities in addition to the underlying malignancy were also frequently present as were concomitant medications; ventricular repolarization abnormalities may have been contributory factors. Hepatic impairment or previous history of pancreatitis; interrupt treatment in case of lipase elevations accompanied by abdominal symptoms; should not be used during pregnancy; sexually active males or females/women of child-bearing potential should be advised to use highly effective contraception while receiving Tasigna and for up to 2 weeks after ending treatment; not recommended in breast-feeding and in patients with rare hereditary problems of galactose intolerance, or severe lactase deficiency or of glucose-galactose malabsorption; the bioavailability of nilotinib might be reduced in patients with total gastrectomy. Interactions: numerous (see full Product Information) including concomitant use with drugs known to prolong the QT interval

† FAST Median time to first MR 4.5 reached 1.3 years faster than imatinib (p<0.0001) 1,4

† DEEP The only TKI to get >50% of patients to MR 4.5 by 5 years vs 31% with imatinib (p<0.0001) 1,2

† PROTECTIVE No patient who achieved MR 4.5 progressed to AP/BC (on core treatment; p-value not reported) 1,3

(e.g. chloroquine, methadone, halofantrine, clarithromycin, haloperidol, moxifloxacin, bepridil, pimozide); anti-arrhythmic medicines (e.g. amiodarone, disopyramide, procainamide, quinidine, sotalol); CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, itraconazole, voriconazole, telithromycin); CYP3A4 inducers (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital or St. John’s wort); may be used concurrently with esomeprazole or other proton pump inhibitors and warfarin; exposure to midazolam; drugs affecting P-glycoprotein; avoid grapefruit juice and foods known to inhibit CYP3A4. In concurrent use: the H2 blocker (e.g. famotidine) may be administered approximately 10 hours before and approximately 2 hours after TASIGNA dose, antacids (e.g. aluminum hydroxide, magnesium hydroxide, simethicone) may be administered approximately 2 hours before or approximately 2 hours after TASIGNA dose. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other drugs primarily metabolized by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment may be necessary for drugs that are CYP3A4 substrates and have a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, astemizole, terfenadine, cisapride, quinidine, pimozide, sirolimus and tacrolimus) when co-administered with nilotinib. Due to possible occurrence of tumour lysis syndrome, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to administration. Side effects: Very common: headache, nausea, constipation, diarrhoea, vomiting, rash, pruritus, alopecia, myalgia, arthralgia, fatigue, upper abdominal pain, myelosuppression (thrombocytopenia, neutropenia), hypophosphataemia (including blood phosphorus decreased), hyperbilirubinaemia (including blood bilirubin increased), alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including low density and high density) increased, total cholesterol increased, blood triglycerides increased. Common: decreased appetite, abdominal pain, muscle spasms, bone pain, pain in extremity, asthenia, oedema peripheral, folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis), skin papilloma, leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia, anaemia, electrolyte imbalance (including hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia, hypomagnesaemia), hyperglycaemia, diabetes mellitus, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridemia, insomnia, depression, anxiety, dizziness, peripheral neuropathy, hypoaesthenia, paraesthesia, eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia), vertigo, angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged, flushing, hypertension, dyspnoea, dyspnoea exertional, epistaxis, cough, dysphonia, abdominal discomfort, dyspepsia, dysgeusia, flatulence, abdominal distension, pancreatitis, hepatic function abnormal, night sweats, hyperhidrosis, dry skin, eczema, urticaria, erythema, dermatitis (including allergic, exfoliative and acneiform), contusion, acne, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness, blood creatine kinase (CK) increased, pollakiuria, pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise, haemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, blood insulin increased, weight decreased, weight increased, globulins decreased. (See full Product Information). Based on approved Tasigna Product Information dated 15 April 2016. For the most up to date Product Information go to http://www.novartis.com.au/products_healthcare.html Tas150416m.doc *Please note changes in Product Information. References: 1. Hochhaus A et al. Leukemia. 2016;30:1044–54. 2. Cortes J et al. J Clin Oncol 2016;34:2333–40. 3. Kantarjian HM et al. Lancet Oncol 2011;12:841–51. 4. Hughes TP et al. Efficacy and safety of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: 6-year follow-up of ENESTnd. Poster presentation at the 20th Annual European Association Congress; June 11–14, 2015; Vienna, Austria.

Novartis Pharmaceuticals Australia Pty Limited ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555. For medical enquiries please contact 1800 671 203 or medinfo.phauno@novartis.com. Tasigna ® is a Registered Trademark of Novartis Pharmaceuticals Pty Limited. AU-0722. NOT0023. Date of preparation: January 2017.