Key Advances in Medicine 2015

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January 2016

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CONTENT A V AILA BLE ONLINE

Nature Publishing Group | Medical Portfolio

World class journals at the forefront of clinical medicine

From cardiology to urology

• Cardiology

• Endocrinology

• Gastroenterology & Hepatology

• Nephrology

• Neurology

• Oncology

• Rheumatology

• Urology

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CLINICAL ONCOLOGY

12 BREAST CANCER IN 2015 Academic research sheds lighton issues that matter to patientsMartine J. Piccart and Isabelle Gingras

14 COLORECTAL AND GASTRIC CANCER IN 2015 Thedevelopment of new agents and molecular classificationsEric Van Cutsem and Michel Ducreux

16 OVARIAN CANCER IN 2015 Insights into strategies foroptimizing ovarian cancer careRobert L. Coleman

18 METASTATIC PROSTATE CANCER IN 2015 The new andthe old that is new again Julie N. Graf and Tomasz M. Beer

20 LUNG CANCER IN 2015 Bypassing checkpoints,overcoming resistance, and honing in on new targetsEgbert F. Smit and Paul Baas

22 MELANOMA IN 2015 Immune-checkpoint blockade— durable cancer controlElizabeth I. Buchbinder and F. Stephen Hodi

GASTROENTEROLOGY

& H E P A T O L O G Y

35 REGENERATIVE MEDICINE IN 2015 Generating andregenerating the digestive system James M. Wells

37 LIVER FIBROSIS IN 2015 Crucial steps towardsan effective treatmentKlaas Poelstra

39 GUT MICROBIOTA IN 2015 Prevotella in the gut:choose carefullyRuth E. Ley

40 HCV IN 2015 Advances in hepatitis C researchand treatmentBarbara Rehermann

42 GASTROINTESTINAL IMAGING IN 2015 Emerging trendsin endoscopic imagingBishnu P. Joshi and Thomas D. Wang

44 PANCREATIC CANCER IN 2015 Precision medicine inpancreatic cancer — fact or fiction?Thomas Seuferlein and Julia Mayerle

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Key Advances in Medicine January 2016

The articles included in Nature Reviews Key Advances in Medicine were originally

published online and appear in the February 2016 issues of the eight clinicalNature Reviews journals. The journals’ editors commissioned international experts

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CARDIOLOGY

1 ARRHYTHMIAS IN 2015 Advances in drug, ablation,and device therapy for cardiac arrhythmiasLaurent Macle and Stanley Nattel

3 CORONARY INTERVENTION IN 2015 Improvementof long-term outcomes after PCIUwe Zeymer

4 CARDIAC RESUSCITATION IN 2015 Improving outcomesafter OHCA — targeting the laypersonClion W. Callaway

6 GENETICS OF CVD IN 2015 Using genomic approachesto identify CVD-causing variantsDonna K. Arnett

8 DYSLIPIDAEMIA IN 2015 Advances in treatmentof dyslipidaemia

Scott M. Grundy

9 HEART FAILURE IN 2015 Better results from preventionthan from additional treatmentLars Køber

ENDOCRINOLOGY

24 OBESITY IN 2015 Advances in managing obesity John B. Dixon

26 THYROID CANCER IN 2015 Molecular landscape ofthyroid cancer continues to be decipheredYuri E. Nikiforov

27 ENDOCRINE DISRUPTORS IN 2015 Epigenetictransgenerational inheritanceMichael K. Skinner

29 HEPATIC GLUCOSE METABOLISM IN 2015 Nutrient andhormone-sensing-dependent regulationTony K. T. Lam

31 ISLET-CELL BIOLOGY IN 2015 Understanding secretion,ageing and death in β cellsGordon C. Weir

33 PCOS IN 2015 New insights into the genetics ofpolycystic ovary syndromeRicardo Azziz

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NEPHROLOGY

46 PODOCYTE BIOLOGY IN 2015 New insights intothe mechanisms of podocyte health Jerey H. Miner

48 IMMUNE REGULATION OF KIDNEY DISEASE IN 2015 Updates on immunosuppression in kidney diseaseHans-Joachim Anders

50 STEM CELLS AND RENAL DEVELOPMENT IN 2015 Advances in generating and maintaining nephronprogenitorsRyuichi Nishinakamura

51 RENAL FIBROSIS IN 2015 Understanding the mechanismsof kidney fibrosisDong Zhou and Youhua Liu

53 HYPERTENSION IN 2015

Resistant hypertension: impactand evolving treatment optionsLilach O. Lerman and Stephen C. Textor

RHEUMATOLOGY

68 GLUCOCORTICOIDS IN 2015 New answers to oldproblemsSarah A. Jones and Eric F. Morand

69 SYSTEMIC LUPUS ERYTHEMATOSUS IN 2015 Cellular andmetabolic requirements of effector T cellsGeorge C. Tsokos

71 PSORIATIC ARTHRITIS IN 2015 Advancement continuesin imaging, tight control and new drugsIgnazio Olivieri and Salvatore D’Angelo

73 INFLAMMATION IN RHEUMATOLOGY IN 2015

New toolsto tackle inflammatory arthritisCharles A. Dinarello and Leo A. B. Joosten

NEUROLOGY

56 PARKINSON DISEASE IN 2015 Evolving basic,pathological and clinical concepts in PDLorraine V. Kalia and Anthony E. Lang

58 STROKE IN 2015 Acute endovascular recanalizationtherapy comes of age Alejandro A. Rabinstein

60 NEURO-ONCOLOGY IN 2015 Progress in glioma

diagnosis, classification and treatmentPatrick Y. Wen and David A. Reardon

61 MULTIPLE SCLEROSIS IN 2015 Managing the complexityof multiple sclerosisOlga Ciccarelli and Alan Thompson

63 EPILEPSY IN 2015 Classic antiepileptic drugs under fire,and new options emergeChristian E. Elger

65 NEURODEGENERATIVE DISEASE IN 2015 Targetingtauopathies for therapeutic translation Julio C. Rojas and Adam L. Boxer

UROLOGY

76 SEXUAL DYSFUNCTION IN 2015 Recovering sex drivein women — progress and opportunitiesRossella E. Nappi and Francesca Albani

78 BLADDER DYSFUNCTION IN 2015 Novel findingscontinue to challenge researchers and cliniciansRose Khavari and Tim Boone

80 STONES IN 2015 Changes in stone management

— suspending belief for evidenceSapan N. Ambani and Khurshid R. Ghani

81 INFECTION IN 2015 HIV protection with PrEP— implications for controlling other STIsDouglas S. Krakower and Kenneth H. Mayer

83 BLADDER CANCER IN 2015 Improving indication,technique and outcome of radical cystectomy J. Alfred Witjes

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Catheter ablation is used increasingly for themanagement of atrial f ibrillation (AF). Overthe past year, results of important random-ized trials of catheter-ablation approacheshave been published. Investigators in theSTAR-AF II study 1 compared three strat-egies of radiofrequency ablation for persis-tent AF in 589 patients randomly assigned topulmonary- vein isolation alone, pulmonary-

vei n isolation plus addit ional lef t atr iallinear ablation, or pulmonary-vein isolationplus ablation of complex fractionated electro-grams. After 18 months, no significant differ-ences were found in the rate of AF recurrence:49% of patients were free from documentedatrial arrhythmia with pulmonary-vein iso-lation alone, versus 37% with additionallinear ablation and 41% with ablation ofcomplex fractionated electrograms (P = 0.15)1.Therefore, additional ablation (of the types

tested) does not improve outcomes comparedwith pulmonary-vein isolation alone in per-sistent AF. Whether more recently developedmethods, such as rotor or rotor-region abla-tion, provide added value to that achievedwith pulmonary-vein isolation remains to bedetermined in randomized trials.

Arrhythmia recurrences after pulmonary- vein ablation are commonly associated withrecovery of pulmonary-vein conduction. Theuse of intravenous adenosine to identify veinsat risk of reconnection for additional abla-tion and thereby improve long-term efficacy

no further ablation (absolute risk reduction27.1%; P 100 years, continuing concerns exist aboutits potential risks. Washam and colleaguesreported a retrospective analysis of 14,171patients in the ROCKET-AF trial4. Digoxinwas used at baseline in 5,239 patients, whowere more likely to be female, and to haveheart failure, chronic obstructive pulmonary disease, diabetes mellitus, and persistent AF.After adjustment, baseline digoxin use wasassociated with increased mortality dur-ing follow-up (5.4% versus 4.3%; adjusted

HR 1.17, 95% CI 1.04–1.32, P = 0.0093)4.

of pulmonary-vein isolation was evaluatedin the ADVICE trial2. In this study, adeno-sine revealed ‘dormant’ pulmonary veinsin 53% of 534 patients with paroxysmal AF.After 12 months, 69.4% of patients randomlyassigned to additional adenosine-guided abla-tion were free from arrhythmia recurrence,compared with 42.3% of patients assigned to

A R R H Y T H M I A S I N 2 0 1 5

Advances in drug, ablation,and device therapy for cardiacarrhythmiasLaurent Macle and Stanley Nattel

Cardiac arrhythmias produce considerable morbidity and mortality, and are

challenging to treat. Advances reported in 2015 will help to guide physiciansin the use of therapeutic approaches ranging from established

pharmaceutical agents through ablation of arrhythmic sources to novel

uses of implanted devices for life-threatening bradyarrhythmias

and tachyarrhythmias.

Ablation

Devices

Drugs

Figure 1 | Therapies for cardiac arrhythmias.

The three major classes of therapeutic approach

currently available and in development:

antiarrhythmic drugs, catheter ablation,

and implanted rhythm-restoration devices.

KEY ADVANCES IN MEDICINE JA NU ARY 20 16 | 1

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In a nationwide population-based study,101,243 patients with AF and receivingrate-control treatments were compared with168,678 patients with AF who were notreceiving rate-control drugs5. Patients receiv-ing digoxin alone had an adjusted mortalityrisk of 1.12 (95% CI 1.10–1.14, P


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Percutaneous coronary intervention (PCI) has

emerged as the revascularization therapy ofchoice in the majority of patients with stablecoronary artery disease and acute coronary syn-dromes1. With the development of new inter-

ventional techniques and devices, even complexlesions such as chronic total occlusions, leftmain stenosis, and bifurcation lesions can betreated with high acute procedural success rates.However, two major issues related to outcomesafter PCI still remain. The introduction of bare-metal stents and drug-eluting stents (DES) hasdiminished, but not completely eliminated, theproblem of early and late restenosis2. Whetherthe need for long-term target-lesion revascu-larization owing to restenosis and acute ischae-mic events can be further reduced is unknown.In addition, although prolonged dual antiplate-let therapy (DAPT) for >12 months results ina further decrease in very late stent thrombo-sis and ischaemic events, it is also associatedwith an increase in bleeding complications3.Therefore, the optimal duration of DAPTremains to be determined.

Bioabsorbable vascular scaffolds (BVS)were developed to improve long-term out-comes after PCI. The occurrence of late adverseevents (restenosis and stent thrombosis) with

permanent metallic stents might be related topersistent inflammation, loss of normal vesselcurvature, impaired vasomotion, strut frac-ture, ongoing tissue growth within the stentframe, and neoatherosclerosis. To overcomethese problems, BVS were developed to pro-

vide mechanical support and optimal drugdelivery associated with excellent mid-termresults, followed by complete bioresorptionover several years.

In the ABSORB-3 multicentre, random-ized trial4, the Absorb BVS (Abbott Vascular,USA) — the first BVS approved for commercial

use — was compared with a third-generation

DES in 2,008 patients with stable or unstableangina. High-risk patients, as determined bytheir clinical presentation or lesion character-istics, were excluded. During the initialPCI procedure, fewer BVS than DES wereimplanted (6.2% versus 0.9%; P = 0.001),owing to reduced deliverability. The primaryend point of target-lesion failure after 1 yearwas not significantly different between theBVS and DES groups in the intention-to-treatanalysis (7.8% versus 6.1%; P= 0.16), or in theas-treated analysis (8.0% versus 6.1%; P = 0.12).Furthermore, although the overall rate of stentthrombosis after 1 year was not significantlydifferent between the BVS-treated patients andthe DES-treated patients (1.5% versus 0.7%;P = 0.13), more subacute stent thrombosisevents occurred with the use of BVS (0.9% ver-sus 0.1%; P = 0.04). Patient-reported angina wassimilar in the two groups after 1 year (18.3%

versus 18.4%). These results suggest that BVSare, at best, as effective and safe as third-gener-ation DES during 1-year of follow-up. WhetherBVS have long-term advantages over DES needsfurther study. Additional improvements in the

design of BVS might improve deliverability andreduce subacute stent thrombosis5. However,for the time being, third-generation DESremain the standard of care for efficacy, safety,and economical reasons.

One drawback of DES has been the need fora longer duration of DAPT, owing to delayedhealing and endothelialization of the coronaryartery compared with bare-metal stents. Thefirst-generation DES have been associatedwith higher rates of late stent thrombosisand, therefore, DAPT for 12 months has beenrecommended after implantation of thesestents1. With the advent of third-generationDES, shorter durations of DAPT have beentested and shown to be safe6. In a study pub-lished in 2015, a new polymer-free and carrier-free DES was tested against a bare-metal stentin 2,466 patients with high risk of bleeding,owing to advanced age (>75 years), the needfor concomitant oral anticoagulation, or

impaired renal function7. DAPT was stoppedafter 30 days, and patients were given singleantiplatelet therapy. Clinically driven target-lesion revascularization, the primary efficacyend point, occurred less often with the DEScompared with the bare-metal stent (5.1%

versus 9.8%; P = 0.001), whereas definite orprobable stent thrombosis (2.0% versus 2.2%)and bleeding events (13.9% versus 14.7%) werenot significantly different7. The primary safetyend point of cardiac death, myocardial infarc-tion, or stent thrombosis occurred less oftenwith the DES (9.4% versus 12.9%; P = 0.005).Given these results, there seems to be no indi-cation favouring bare-metal stents over DES,irrespective of patient and lesion subset.

The optimal duration of DAPT after PCI isstill a matter of debate. The benefit of extend-ing antiplatelet therapy to reduce the risk ofcardio vascular events must be carefully bal-anced against the associated increased risk ofbleeding complications. The DAPT trial3, inwhich patients were randomized 12 monthsafter DES implantation to placebo or a pro-longed administration of DAPT, showed a

Table 1 | Suggested duration of dual antiplatelet therapy

DAPT duration Patient profile

1 month Elective PCI with bare-metal stent, or third-generation drug-eluting stentwith high bleeding risk

3 months Elective PCI with third-generation drug-eluting stent and increased bleedingrisk, or bleeding event 12 months PCI for acute coronary syndromes in patients with diabetes mellitus,renal insufficiency, and/or DAPT score >2

DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.

CORONARY INTERVENTION IN 2015

Improvement of long-termoutcomes after PCIUwe Zeymer

Third-generation drug-eluting stents (DES) have emerged as first-line

devices for percutaneous coronary intervention, even in patients with high

bleeding risk. Studies published in 2015 report that bioabsorbable vascular

scaffolds are equally effective and safe as DES in low-risk populations and,

with the addition of extended dual antiplatelet therapy, might improve

long-term outcomes.


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CARDIAC RESUS CITATION IN 2015

Improving outcomes after OHCA— targeting the layperson

Clifton W. Callaway

The proportion of the lay population that is trained in cardiopulmonary

resuscitation is closely linked to the probability of an individual surviving

cardiac arrest. New mobile-assisted technologies might increase the benefit

of population-based training. Furthermore, admission of patients to

specialized hospitals can increase the likelihood of survival.

reduction in stent thrombosis and an increasein bleeding complications in patients receivingextended DAPT. A study published in 2015

that was prematurely terminated8 reportedonly trends for a reduction in ischaemic out-comes, without a difference in bleeding events,after extending DAPT from 12 up to 48 months(median 33 months).

In a meta-analysis involving 33,435 patientswith a history of myocardial infarction,extended DAPT significantly reduced cardio-

vascular death (risk ratio [RR] 0.85, 95% CI0.74–0.98), stroke (RR 0.81, 95% CI 0.68–0.97),myocardial infarction (RR 0.70, 95% CI 0.55–0.88), and stent thrombosis (RR 0.50, 95% CI0.28–0.89)9. An increase in major bleedingcomplications was observed in patients whoreceived extended DAPT (RR 1.73, 95% CI1.19–2.50), but no increase occurred in fatalbleeding (RR 0.91, 95% CI 0.53–1.58) or all-cause mortality (RR 0.92, 95% CI 0.83–1.03).These data suggest that whereas DAPT forshorter durations (3–6 months) after electivePCI seems favourable, extended DAPT beyond12 months (up to 36–48 months) should beconsidered after PCI in patients with acutecoronary syndromes, if well-tolerated withinthe first 12 months (TABLE 1).

These studies published in 2015 providedfurther evidence for the efficacy and safety of

third-generation DES in all patient and lesionsubsets, whereas BVS might have the potentialto improve long-term outcomes even further.Growing evidence indicates that extendedDAPT for >12 months after PCI for acute coro-nary syndrome is favourable in selected patientswith high ischaemic and low bleeding risk.

Uwe Zeymer is at Klinikum Ludwigshafen and the

Institut für Herzinfarktforschung Ludwigshafen,

Bremser Strasse 79, 67063 Ludwigshafen, Germany.

[email protected]

doi:10.1038/nrcardio.2015.204

Published online 14 Jan 2016

1. Windecker, S. et al. 2014 ESC/EACTS Guidelines

on myocardial revascularization. Eur. Heart J. 35,

2541–2619 (2014).2. Sabaté, M. et al. Clinical outcomes in patients with

ST-segment elevation myocardial infarction treated

with everolimus-eluting stents versus bare-metal

stents (EXAMINATION): 5-year results of a

randomised trial. Lancet http://dx.doi.org/10.1016/

S0140-6736(15)00548-6 (2015).

3. Mauri, L. et al. Twelve or 30 months of dual

antiplatelet therapy after drug-eluting stents. N. Engl.

J. Med.371, 2155–2166 (2014).4. Ellis, S. G. et al. Everolimus-eluting bioresorbable

scaffolds for coronary artery disease. N. Engl. J. Med.

373, 1905–1915 (2015).

5. Haude, M. et al. Safety and performance of the

second-generation drug-eluting absorbable metal

scaffold in patients with de-novo coronary artery

lesions (BIOSOLVE-II): 6 month results of a

prospective, multicentre, non-randomised,

first-in-man trial. Lancet http://dx.doi.org/10.1016/

S0140-6736(15)00447-X (2015).

6. Kim, B. K. et al. A new strategy for discontinuation of

dual antiplatelet therapy: the RESET Trial (REal Safety

and Efficacy of 3-month dual antiplatelet Therapy

following Endeavor zotarolimus-eluting stent

implantation). J. Am. Coll. Cardiol. 60, 1340–1348

(2012).

7. Urban, P. et al. Polymer-free drug-coated coronary

stents in patients at high bleeding risk. N. Engl.

J. Med. 373, 2038–2047 (2015).

8. Helft, G. et al. Stopping or continuing clopidogrel

12 months after drug-eluting stent placement:

the OPTIDUAL randomized trial. http://dx.doi.org/

10.1093/eurheartj/ehv481 (2015).

9. Udell, J. A. et al. Long-term dual antiplatelet therapyfor secondary prevention of cardiovascular events in

the subgroup of patients with previous myocardial

infarction: a collaborative meta-analysis of randomized

trials. Eur. Heart J. http://dx.doi.org/10.1093/

eurheartj/ehv443 (2015).

Competing interests statementU.Z. declares that he has received speaker fees from

Ast raZeneca, B. Brau n, Baye r Hea lthcar e, Bio tronik ,

Boehringer Ingelheim, Bristol-Myers Squibb, Correvio, Daiichi

Sankyo, Eli Lilly, Hexal, Medtronic, The Medicines Company,

MSD, Novartis, Pfizer, and Sanofi.

Key advances

• The bioabsorbable vascular scaffold

Absorb was as safe and effective as a

third-generation drug-eluting stent in a

low-risk percutaneous coronary intervention

(PCI) population during 1 year follow‑up4

• A polymer-free and carrier-free drug-coated

stent with a reduced duration of dualantiplatelet therapy of 4 weeks was as safe

and more effective than a bare-metal stent

in patients with high bleeding risk7

• In patients treated with PCI for acute

coronary syndromes, longer term dual

antiplatelet therapy beyond 12 months

further reduces ischaemic events and

stent thrombosis9

In 2015, numerous cohort studies revealedthe potential for system-level interventionsto improve outcomes after cardiopulmonaryresuscitation (CPR). Several of these reportsfocused on long-term and short-term strat-egies to mobilize layperson rescuers, whereasother studies examined how survival outcomescan be influenced by the choice of hospital inwhich a patient is treated immediately aftercardiac arrest. Results from these studies sup-port the 2015 Institute of Medicine recommen-dations on strategies to improve survival aftercardiac arrest, which highlighted the impor-tance of using regional and national databases,

fostering a culture of action among laypersons,setting accreditation standards for health-caresystems, and implementing continuous qualityimprovement programmes1.

During a cardiac arrest, the heart stopspumping blood because of mechanical orelectrical disturbances. Total body ischaemiaaffects every organ system, and cardiac arrest isfatal unless rapidly reversed. Although patientscan tolerate long total durations of CPR whenit is initiated immediately, delays of even a fewminutes in initiating CPR can lead to cellularenergy depletion and vascular collapse that

are difficult to reverse, reducing the chances ofneurological recovery and survival2. Given thatprofessional medical personnel often arrivetoo late to initiate CPR for all patients, severalstudies published in 2015 sought to examinethe value of recruiting laypersons to adminis-ter CPR and improve survival outcomes afterout-of-hospital cardiac arrest (OHCA).

Hasselqvist-Ax and colleagues describedlayperson CPR in Sweden from 1990 to 2011using a national database of OHCA events3.The proportion of citizens trained in CPRincreased over this period as a result ofgovernment-funded initiatives, including

widespread public training and implemen-tation of telephone-assisted CPR whereinemergency call-takers instruct the caller onhow to perform chest compressions whileawaiting ambulance arrival. Consequently, theproportion of patients experiencing cardiacarrest who received layperson CPR increasedfrom 35% to 65%. Among cases where col-lapse was witnessed, laypersons performedCPR in 51.1% (15,512 of 30,381) of patients,for whom 30-day mortality was 10.5%.Conversely, 30-day mortality in patients whodid not receive CPR until paramedic assistance

4 | JANUARY 2016 www.nature.com/reviews

CARDIOLOGY

mailto:[email protected]://dx.doi.org/10.1038/nrcardio.2015.204http://dx.doi.org/10.1016/S0140-6736(15)00548-6http://dx.doi.org/10.1016/S0140-6736(15)00548-6http://dx.doi.org/10.1016/S0140-6736(15)00548-6http://dx.doi.org/10.1016/S0140-6736(15)00548-6http://dx.doi.org/10.1016/S0140-6736(15)00447-Xhttp://dx.doi.org/10.1016/S0140-6736(15)00447-Xhttp://dx.doi.org/10.1093/eurheartj/ehv443http://dx.doi.org/10.1093/eurheartj/ehv443http://dx.doi.org/10.1093/eurheartj/ehv443http://dx.doi.org/10.1093/eurheartj/ehv443http://dx.doi.org/10.1016/S0140-6736(15)00447-Xhttp://dx.doi.org/10.1016/S0140-6736(15)00447-Xhttp://dx.doi.org/10.1016/S0140-6736(15)00548-6http://dx.doi.org/10.1016/S0140-6736(15)00548-6http://dx.doi.org/10.1038/nrcardio.2015.204mailto:[email protected]


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arrived was significantly lower (4.0%; OR 2.15,95% CI 1.88–2.45)3. Similar national datafrom 167,912 patients in Japan between 2005and 2012 have also been reported4. Rates oflayperson CPR for patients witnessed to col-lapse increased from 38.6% to 50.9% over thistime period, and rates of functionally favour-able survival increased from 3.3% to 8.2%.Functionally favourable survival rate was 8.4%(6,594 of 78,592 patients) with layperson CPR

versus 4.1% (3,595 of 88,720 patients) withoutlayperson CPR (OR 1.52, 95% CI 1.45–1.60)4.

The USA does not have comprehensivenational data on responses to OHCA events,but layperson rescue in North Carolinahas been described for the period between2010 and 2013 using a database of 4,961patients5. During this time period, state-funded initiatives encouraged laypersonCPR, telephone-assisted CPR, and dispatchof non-medical public safety providers (policeand firefighters) to assist in cases of OHCA.The overall rate of survival with favourable

neurological outcome increased from 7.1%(82 of 1,149 patients) in 2010 to 9.7% (129of 1,334 patients) in 2013 (REF. 5). The rate ofsurvival to hospital discharge among patientswho received layperson CPR was 11.8%(266 of 2,250 patients) compared with 8.9%(178 of 1,994 patients) for individuals withfirst responder-initiated CPR and 7.6% (51 of672) for emergency medical services-initiatedCPR (P


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interventions that treated ≥40 cases of OHCAper year (n = 54). In total, 24% of patients inthe study had good functional recovery, butno clear association existed between the num-ber of patients with OHCA admitted to eachhospital and outcome. Treatment at a cardiaccentre that treated ≥40 cases of OHCA year(OR 1.32, 95% CI 1.06–1.64) and 50%,and that cheap, ready-to-implement interven-tions such as SMS and telephone-assisted CPRcan immediately increase layperson response.With improved layperson response, survivalmight be possible for >10% of patients. Finally,admission of patients after OHCA to hospi-tals that provide high-intensity care afterCPR is associated with increased survival.Policies and incentives to promote laypersonresponse and encourage accountable hospitalcare will lead to more lives being saved.

Clifton W. Callaway is at the Department of Emergency

Medicine and Department of Pharmacology and

Chemical Biology, University of Pittsburgh,

Iroquois 400A, 3600 Forbes Avenue,

Pittsburgh, Pennsylvania 15260, USA.

[email protected]

doi:10.1038/nrcardio.2015.201


1. Neumar, R. W. et al. Post-cardiac arrest syndrome:

epidemiology, pathophysiology, treatment, and

prognostication. Circulation 118, 2452–2483

(2008).

2. Graham, R., McCoy, M. A. & Schultz, A. M. Strategies

to Improve Cardiac Arrest Survival: A Time to Act

(The National Academies Press, 2015).

3. Hasselqvist-Ax, I. et al. Early cardiopulmonaryresuscitation in out-of-hospital cardiac arrest. N. Engl.

J. Med. 372, 2307–2315 (2015).4. Nakahara, S. et al. Association of bystander

interventions with neurologically intact survival among

patients with bystander-witnessed out-of-hospital

cardiac arrest in Japan. JAMA 314, 247–254 (2015).

5. Malta Hansen, C. et al. Association of bystander

and first-responder intervention with survival after

out-of-hospital cardiac arrest in North Carolina:

2010–2013. JAMA 314, 255–264 (2015).

6. Ringh, M. et al. Mobile-phone dispatch of laypersons

for CPR in out-of-hospital cardiac arrest. N. Engl.

J. Med. 372, 2316–2325 (2015).

7. Callaway, C. W. et al. Part 8: post-cardiac arrest care:

2015 American Heart Association guidelines update

for cardiopulmonary resuscitation and emergency

cardiovascular care. Circulation 132 (Suppl. 2),

S465–S482 (2015).

8. Kronick, S. L. et al. Part 4: systems of care and

continuous quality improvement: 2015 American

Heart Association guidelines update for

cardiopulmonary resuscitation and emergency

cardiovascular care. Circulation 132 (Suppl. 2),

S397–S413 (2015).

9. Søholm, H. et al. Prognostic implications of level-of-care

at tertiary heart centers compared with other hospitals

after resuscitation from out-of-hospital cardiac arrest.

Circ. Cardiovasc. Qual. Outcomes 8, 268–276 (2015).

10. Mumma, B. E., Diercks, D. B., Wilson, M. D.

& Holmes, J. F. Association between treatment

at an ST-segment elevation myocardial infarction

center and neurologic recovery after

out-of-hospital cardiac arrest. Am. Heart J. 170,

516–523 (2015).

AcknowledgementsC.W.C. is supported by NHLBI grants U01 HL077871 and

K12 HL109068.

Competing interests statementC.W.C. is the Chair of Emergency Cardiovascular Care

Committee for the AHA.

Multilayered ‘-omic’ approaches are prov-ing successful for the identification of newgenetic contributors to cardiovascular dis-eases (CVDs), and for furthering our under-standing of the mechanisms linking knowngenetic mutations to disease causation. Thethree most important papers in cardiovasculargenetics for 2015 highlight the value of differ-ent and complementary genomic approachesto delineate the causes underlying complexCVDs. Coronary artery disease (CAD), themost common cause of cardiovascular deathglobally 1, has been the focus of several genomicstudies. Furthermore, the genetic mutationsunderlying the pathogenesis of dilated cardio-myopathy (DCM), one of the most commoncardiomyopathies and the most frequent indi-cation for cardiac transplantation, has alsoreceived considerable interest. Together, thesestudies demonstrate remarkable progress in the

past year in defining the genetic architectureof CVD, and offer novel pathways for futureprevention and treatment options.

CAD has been a frequent subject ofgenomic inquiry. Genome-wide associ-ation studies (GWAS) of common single-nucleotide polymorphisms (SNPs) have thusfar identified 48 genome-wide significant lociassociated with CAD2,3. Investigators in theCARDIoGRAMplusC4D consortium con-ducted a large meta-analysis of CAD usingphased haplotypes from the 1000 GenomesProject4. Data from 60,801 patients with CAD

(myocardial infarction [MI], acute coronarysyndrome, chronic stable angina, or coro-nary stenosis of >50%) and 123,504 controlswere collated from 48 studies. The analysisincluded common variants (n = 6.7 millionwith minor allele frequency [MAF] >0.05)and low frequency variants (n = 2.7 millionwith 0.005


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confirmed 47 of 48 previously reported genesat a nominal significance level. The majority(98.3%) of the significant loci were common

variants. However, owing to the increasedprecision of imputation afforded by the 1000Genomes Project, rare frequency SNPs in APOE and PCSK9 showed strong associationsthat were overlooked in the HapMap-basedGWAS2,3. The CARDIoGRAMplusC4D con-sortium identified eight new loci from theiradditive models. These loci were biologi-cally relevant and valid candidate genes withwell-documented roles in vessel wall biology,including cell adhesion, leukocyte and vascularsmooth muscle cell migration, vascular smoothmuscle cell phenotypic switching, transforminggrowth factor-β signalling, angiogenesis, andnitric oxide signalling. These candidate genesare also known to have anti-inflammatory andinfarct-sparing effects.

The large sample size in this study also

allowed exploration of recessive and dominantmodes of inheritance. Using a recessive inherit-ance model to determine susceptibility to CADfrom homozygosity for the less frequent allele,two new recessive loci were identified, neitherof which were significant using an additivemodel. The dominant inheritance modelidentified variants that had been detected withthe additive analysis. Together, these resultssuggest that CAD is largely determined bycommon SNPs with small effect sizes.

Inherited genetic factors are thought tocontribute to MI that occurs early in life5.Common variants in approximately 45 genesand rare variants in LDL-related genes havepreviously been associated with early MI6. Doand colleagues used a range of approaches toevaluate how low-frequency and rare vari-ants across the genome contribute to risk ofearly MI6. Using whole-exome sequencing,the investigators sequenced all protein-codinggenes in 1,027 patients with early MI (men aged≤50 years, women aged ≤60 years) and 946 olderMI-free controls (men aged ≤60 years, womenaged ≤70 years). On average, each person had43 nonsense, 7,828 missense, 92 splice-site, 189indel frameshift, 366 indel nonframeshift, and

103 nonsynonymous singleton variants. Noneof the approximately 20,000 genes analysed inthe discovery set was significant.

The discovery sequencing results werefollowed up using four different approaches6.The first (statistical imputation in 64,132patients and controls) and second (analysingthe Illumina Exome chip in 15,936 patientsand controls) approaches did not producesignificant findings for low-frequency vari-ants. In their third approach, the investigatorsconducted targeted resequencing of APOA5 in6,721 patients and 6,711 controls. Using burden

tests for an excess (or deficit) of aggregated rare(


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DYSLIP IDAEMIA IN 2015

Advances in treatmentof dyslipidaemiaScott M. Grundy

Statins remain the first-line therapy for dyslipidaemia. In 2015, however,

effectiveness in reducing serum cholesterol levels and decreasing rates of

cardiovascular disease in combination with statins has been demonstrated

for two new classes of drugs: cholesterol-absorption inhibitors and PCSK9

inhibitors. The latter rival statins in their capacity to lower cholesterol levels.

Findings from a meta-analysis and three sem-inal, randomized, controlled trials (RCTs) pub-lished in 2015 have far-reaching implicationsfor the management of cholesterol levels. In the

past 3 decades, cholesterol-lowering therapyhas been dominated by statins. These drugsreduce LDL-cholesterol (LDL-C) levels withfew adverse effects. RCTs document their effi-cacy in reducing atherosclerotic cardiovasculardisease (ASCVD). Several statins are now avail-able as inexpensive, generic drugs. Statins arethe standard of care for secondary preventionof ASCVD, and are being used increasinglyin primary prevention. They inhibit choles-terol synthesis and reduce hepatic cholesterolcontent, which increases expression of LDLreceptors and lowers serum LDL-C level. High-intensity statins can reduce LDL-C levels byup to 60%. Two other drugs, ezetimibe andinhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), also lower LDL-C levelsthrough their actions on LDL receptors (FIG. 1).

A meta-analysis by the CholesterolTreatment Trialists’ (CTT) Collaborationshowed that statin therapy is equally efficaciousin reducing major cardiovascular events inmen as in women1. In this analysis, relative riskof vascular events was reduced by 22% in menand by 16% in women for every 1.0 mmol/l(38.6 mg/dl) decrease in LDL-C level. Noadverse effects on cancer or noncardiovascular

mortality were found in either men or women.This meta-analysis confirms that for every1% reduction in the LDL-C level, the risk ofevents related to ASCVD is reduced by ~1%.Consequently, a 50% decrease in LDL-C levelwith high-intensity statins should reduce therisk of ASCVD by ~50%, a benefit that appliesequally to men and women. However, thefindings sparked another question, namelywhether further reduction in LDL-C levels,beyond those achieved by treatment with high-intensity statins, would yield an additionalreduction in risk.

To address this question, investigatorsperformed the randomized, controlledIMPROVE-IT trial2, in which the combinationof simvastatin (40 mg) and ezetimibe (10 mg)

was compared with simvastatin (40 mg) andplacebo. A total of 18,144 patients, hospital-ized for an acute coronary syndrome eventwithin the preceding 10 days and who had anLDL-C level of 1.3–3.3 mmol/l, were recruitedinto the IMPROVE-IT trial, regardless ofprevious treatment with statins. The meanLDL-C level was 53.7 mg/dl (1.4 mmol/l) inpatients receiving combination therapy, and69.5 mg/dl (1.8 mmol/l) in those receivingstatin monotherapy. Compared with statintherapy alone, combined therapy significantlyreduced the risk of future ASCVD events

Figure 1 | Statins, ezetimibe, and PCSK9

inhibitors all increase the expression of LDL

receptors and reduce LDL‑cholesterol

levels (by percentages shown). Statins inhibit

cholesterol synthesis in the liver, ezetimibe

blocks cholesterol absorption in the intestine,

and proprotein convertase subtilisin/kexin

type 9 (PCSK9) inhibitors block thePCSK9-mediated degradation of LDL receptors.

Dietarycholesterol

PCSK9inhibitors(40–60%)

Ezetimibe(15–20%)

CholesterolAcetate

Statins(40–60%)

Endosomaldegradation

LDL receptors

LDL

By growing CMTs on flexible and rigid canti-levers (to mimic levels of biomechanical stress)and treating with isoproterenol (to mimicβ-adrenergic stimulation), the investigatorssuggested that TTNtvs can cause decreasedresponse to mechanical load.

Together, these studies indicate that iniPS-CMTs, missense mutations, and TTNtvscan result in forms of sarcomere insufficiencythat can lead to deficits in baseline and stress-response contractile function, factors critical inthe pathogenesis of DCM. The importance ofthis study lies not only in its functional insightswith potentially profound therapeutic value,but in its model integration and scaffolding ofcomplementary microbiological and molecularbiological experimental approaches.

The studies discussed in this article con-tribute to the advancement of cardiovasculargenomics in two ways. First, each study addsto the body of knowledge within its respective

disease domain by identifying novel risk vari-ants or confirming suspected variants (FIG. 1).Furthermore, these studies illustrate thatalthough molecular genomic data might serveas the basis of all future research, adequatelypowered studies combining analytical, func-tional, and bioinformatic techniques need to beintegrated before even the most rudimentarytranslational steps can be undertaken.

Donna K. Arnett is at the UAB School of Public Health,

Department of Epidemiology, University of Alabama at

Birmingham, 220E 1530 3rd Avenue South,

Birmingham, Alabama 35294, USA.

[email protected]

doi:10.1038/nrcardio.2015.202


1. Kessler, T., Erdmann, J. & Schunkert, H. Genetics

of coronary artery disease and myocardial infarction

— 2013. Curr. Cardiol. Rep. 15, 368 (2013).

2. Deloukas, P. et al. Large-scale association analysis

identifies new risk loci for coronary artery disease.

Nat. Genet. 45, 25–33 (2013).

3. The Coronary Artery Disease (C4D) Genetics Consortium.

A genome-wide association study in Europeans and

South Asians identifies five new loci for coronary artery

disease. Nat. Genet. 43, 339–344 (2011).

4. Nikpay, M. et al. A comprehensive 1000 Genomes-

based genome-wide association meta-analysis of

coronary artery disease. Nat. Genet. 47, 1121–1130

(2015).

5. Lloyd-Jones, D. M. et al. Parental cardiovascular

disease as a risk factor for cardiovascular disease

in middle-aged adults: a prospective study of parents

and offspring. JAMA 291, 2204–2211 (2004).

6. Do, R. et al. Exome sequencing identifies rare LDLR

and APOA5 alleles conferring risk for myocardial

infarction. Nature 518, 102–106 (2015).

7. Teslovich, T. M. et al. Biological, clinical and population

relevance of 95 loci for blood lipids. Nature 466,

707–713 (2010).

8. Hinson, J. T. et al. Titin mutations in iPS cells define

sarcomere insufficiency as a cause of dilated

cardiomyopathy. Science 349, 982–986 (2015).

9. Hershberger, R. E., Hedges, D. J. & Morales, A. Dilated

cardiomyopathy: the complexity of a diverse genetic

architecture.Nat. Rev. Cardiol. 10, 531–547 (2013).

10. Herman, D. S. et al. Truncations of titin causing dilated

cardiomyopathy. N. Engl. J. Med. 366, 619–628

(2012).

Competing interests statementThe author declares no competing interests.


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by 6%. The investigators estimated that toachieve a reduction in ASCVD events, thenumber-needed-to-treat was ~51, regarded as

justifiable by many experts.Beyond the practical use of ezetimibe in

combination with statins, the results of theIMPROVE-IT trial demonstrate that risk isreduced proportionately to the reduction inLDL-C level, unrelated to pleiotropic effects ofstatins. Ezetimibe primarily acts on the intes-tine, and has no known systemic effects (FIG. 1).The findings of this trial strongly support the‘cholesterol hypothesis’, which had been blurredto some extent by claims of pleiotropism ofstatins. The authors of an editorial accom-panying the publication of findings from theIMPROVE-IT trial also regarded the reductionin LDL-C level as the dominant action of stat-ins, and proposed the principle of “the lower,the better”3 when assessing levels of LDL-C.The CTT investigators favoured estimatingbenefits in terms of percentage LDL-C lower-ing (“the more, the better”1), whereas the resultsof the IMPROVE-IT trial seemingly support ashift in emphasis to decreasing LDL-C to verylow levels (“the lower, the better”3).

An opportunity to test this new hypothesispresented itself with the introduction of a newclass of drugs. Inhibition of PCSK9 by mono-clonal antibodies allows greater expression ofLDL receptors, which in turn lowers serumLDL-C concentrations (FIG. 1). Two reports

published in 2015 document the efficacy ofPCSK9 inhibitors for reducing the LDL-C level,and findings strongly suggest that they alsodecrease the risk of cardiovascular events4,5.

An RCT to investigate the efficacy of theanti-PCSK9 monoclonal antibody alirocumabincluded 2,341 patients at high risk of cardio-

vascular events who received statins at maxi-mal tolerated doses4. Patients were randomlyassigned in a 2:1 ratio to receive either statinsin combination with 150 mg alirocumab (sub-cutaneously every other week) or statins alone,for 78 weeks. Interim analysis showed that

combination therapy achieved a significantly(62%) greater reduction in LDL-C levels, and a post-hoc analysis showed a 48% greater reduc-tion in major cardiovascular events comparedwith statins alone.

Another PCSK9 inhibitor is evolocumab.In two open-label trials, a total of 4,465high-risk patients were randomly assignedin a ratio of 2:1 to receive either evolocumabplus standard therapy or standard therapyalone5. Patients were followed up for majorcardio vascular events (median 11.1 months).In both trials, mean LDL-C levels were120 mg/dl when receiving standard therapy,whereas addition of evolocumab reducedLDL-C levels by a further 61% to 48 mg/dl.In the two trials combined, the risk of majorASCVD events was reduced by 53% whenreceiving combination therapy compared withstandard therapy. Neurocognitive events werereported more frequently as adverse effects in

patients treated with evolocumab. These trialsare again highly suggestive, although per-haps not definitive, of an added benefit fromPCSK9 inhibitors.

These two reports4,5 influenced the deci-sion of regulatory agencies in Europe and theUSA to approve PCSK9 inhibitors for limitedclinical use. Accepted indications include adultpatients with heterozygous familial hyper-cholesterolaemia and patients with clinicalASCVD who might benefit from a furtherreduction in levels of LDL-C. Beyond theseindications, PCSK9 inhibitors might prove tobe useful in individuals with statin intolerance,a condition that occurs in ~10% of patients.

In 2015, cholesterol research has movedinto a new phase. Statins are well establishedas first-line therapy to lower levels of LDL-Cin patients at risk of ASCVD. However, newtherapies have made it possible to achievegreater reductions in the risk of ASCVD byfurther lowering levels of LDL-C. The bene-fits of combining ezetimibe with statin ther-apy have been firmly established, and PCSK9inhibitors offer even greater potential throughtheir enhanced capacity to lower LDL-C levels.

Scott M. Grundy is at the Center for Human Nutrition

and Department of Internal Medicine,

University of Texas Southwestern Medical Center,

5323 Harry Hines Boulevard, Suite Y3.206,

Dallas, Texas 75390–9052, USA.

[email protected]

doi:10.1038/nrcardio.2015.208


1. Cholesterol Treatment Trialists’ (CTT) Collaboration.

Efficacy and safety of LDL-lowering therapy among

men and women: meta-analysis of individual data from174,000 participants in 27 randomised trials. Lancet385, 1397–1405 (2015).

2. Cannon, C. P. et al. Ezetimibe added to statin therapy

after acute coronary syndromes. N. Engl. J. Med. 372,

2387–2397 (2015).

3. Jarcho, J. A. & Keaney, J. F. Jr. Proof that lower is

better — LDL cholesterol and IMPROVE-IT. N. Engl.

J. Med. 372, 2448–2450 (2015).

4. Robinson, J. G. et al. Efficacy and safety of alirocumab

in reducing lipids and cardiovascular events. N. Engl.

J. Med. 372, 1489–1499 (2015).

5. Sabatine, M. S. et al. Efficacy and safety of

evolocumab in reducing lipids and cardiovascular

events. N. Engl. J. Med. 372, 1500–1509 (2015).

AcknowledgementsS.M.G. is employed and supported by the Veterans Affairs

Medical Center, Dallas, Texas, USA.

Competing interests statementThe author declares no competing interests.

Key advances

• Statin therapy reduces the risk of

atherosclerotic cardiovascular disease

to an equal extent in both men and women1

• Addition of ezetimibe to statins given at

maximum dose further reduces the risk

of cardiovascular disease compared

with statins alone2

• Proprotein convertase subtilisin/kexin

type 9 inhibitors greatly enhance the

reduction of LDL-cholesterol levels, even

when combined with statins, and seem

incrementally to reduce the risk of

atherosclerotic disease4,5

Medical treatment of heart failure has focusedon two phenotypes according to whether ornot left ventricular systolic function is pre-served. Although no drug has shown a con-

vincing benefit in patients with heart failureand preserved ejection fraction, the inhib-ition of the renin–angiotensin system with

angiotensin-converting-enzyme (ACE) inhib-itors or with angiotensin-receptor blockers hasbeen the standard of care for 20 years, mainlyowing to the results obtained in patients withheart failure with reduced ejection fraction(HFrEF). Following the success in 2014 withmodification of the renin–angiotensin system

HEART FAILURE IN 2015

Better results from prevention thanfrom additional treatment

Lars Køber

In 2015, success in clinical trials in heart failure was obtained mainly from

prevention, whereas treatments showed neutral or even adverse effects.A new glucose-lowering medication prevents development of heart failure.

Treating central sleep apnoea might be harmful. In Chagas cardiomyopathy,

benznidazole treatment did not affect long-term clinical outcomes.


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using the new dual angiotensin–neprilysinreceptor inhibitor LCZ696, the prospect ofachieving additional benefits for patientswith HFrEF seemed difficult. This assess-ment turned out to be true, but several veryimportant findings have been made in 2015.

Sleep-disordered breathing is commonin patients with HFrEF. Two distinct typesof sleep-disordered breathing have beendescribed: obstructive sleep apnoea and cen-tral sleep apnoea. Obstructive sleep apnoea isseen more often in patients with HFrEF thanin the general population, and central sleepapnoea is found in 25–40% of patients withHFrEF1. Central sleep apnoea can manifest asCheynes–Stokes respiration and is associatedwith a poor prognosis. Central sleep apnoeais associated with increases in sympatheticnervous system activity and with intermittenthypoxaemia, which can be detrimental to car-diac function. Previous studies have suggestedthat continuous positive airway pressure canreduce mortality in selected patients withHFrEF, and devices are widely used to treatsleep-disordered breathing. Researchers inthe SERVE-HF trial2 investigated whether

adaptive servo-ventilation could reduce therisk of death in patients with moderate-to-severe HFrEF and predominantly centralsleep apnoea. In total, 659 patients wererandomly assigned to the control group toreceive guideline-based treatment alone and666 patients to receive treatment with adap-tive servo-ventilation. The primary end point(composite of death and hospitalization forheart failure) was not different between thetwo groups (HR 1.13, 95% CI 0.97–1.31,P = 0.10), but surprisingly the risk of deathfrom any cause was significantly higher in the

patients treated with adaptive servo- ventilation(HR 1.28, 95% CI 1.06–1.55, P = 0.01) than inthe control group. The mechanism for thisunexpected finding remains to be elucidated,but speculations focus on whether positiveairway pressure might impair cardiac func-tion in patients with low pulmonary wedgepressure. An additional explanation is thatcentral sleep apnoea might be a compensatorymechanism, and reducing this respiratory pat-tern might be harmful. The results from theSERVE-HF trial highlight the importance ofperforming conclusive randomized, controlledtrials; otherwise, harmful treatments would beimplemented on the basis of smaller studies.Thus, the SERVE-HF trial might result in livesbeing saved by preventing the use of adaptiveservo-ventilation in patients with heart failureand central sleep apnoea.

Type 2 diabetes mellitus can cause heartfailure, and heart failure can lead to type 2

diabetes. Treatment of one disease can makethe other worse and, since 2008, regulatoryagencies require robust cardiovascular out-come data from randomized, controlled trialsto approve (or maintain approval of) drugsfor treatment of diabetes. Despite being effec-tive in reducing blood glucose levels, severalstudies have shown that some hypoglycae-mic medications can increase, rather thanreduce, cardiovascular events. Investigatorsin the EMPA-REG OUTCOME study 3 testedtwo dosages of empagliflozin, an inhibitor ofthe sodium/glucose cotransporter 2 (SGLT2)(FIG. 1), against placebo in 7,020 patientswith type 2 diabetes and high cardiovascu-lar risk. The primary outcome (death fromcardiovascular disease, nonfatal myocardialinfarction, or nonfatal stroke) was reducedby 14% (HR 0.86, 95% CI 0.74–0.99, P = 0.04)in the pooled group of patients who receivedempagliflozin compared with the placebogroup. Importantly, both cardiovascular and

all-cause mortality were significantly reducedby 38% and 35%, respectively. Hospitalizationfor heart failure was reduced by 35% (HR 0.65,95% CI 0.50–0.85, P = 0.002) in the empagli-flozin group compared with the placebogroup, and in the 10% of patients with heartfailure at baseline, the results for reduction incardio vascular and all-cause mortality were aspositive as for the overall trial (29% and 21%reduction, respectively). The EMPA-REGOUTCOME study suggests that empagli-flozin can prevent heart failure in patients withtype 2 diabetes, and might also reduce mortal-ity in the high-risk group of patients with bothdiabetes and heart failure.

Dipeptidyl peptidase 4 (DPP4) inhibi-tors have been used in patients with diabetesfor almost 10 years; however, concerns thatthese inhibitors might increase heart failure-related events have been raised. Sitagliptin, aDPP4 inhibitor, was tested against placebo in

the large TECOS trial4 that included 14,671patients with a baseline level of glycatedhaemoglobin (HbA1c) of 6.5–8.0% and withdiagnosed cardiovascular disease. The primarycomposite end point of cardiovascular mor-tality, nonfatal myocardial infarction, nonfatalstroke, or hospitalization for unstable anginawas neutral (HR 0.98, 95% CI 0.88–1.09), witha highly significant P value for noninferiority(P


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6,068 patients with type 2 diabetes and a recentcoronary event in the ELIXA study 5. The pri-mary composite end point of cardio vascularmortality, nonfatal myocardial infarction,stroke, or hospitalization for unstable anginawas similar in the two groups (HR 1.02, 95% CI0.89–1.17) and demonstrated noninferiority(P


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Academic research in oncology, which ispatient-centred and provides answers toquestions with limited or no commercial inter-est, has been under threat in the past decade.However, seven academic clinical trials reportedin 2015 reassure us that research remains alive,and that academic clinical investigators continueto find the energy needed to secure the financialsupport for this critically important research.Through these efforts, questions important topatients with breast cancer regarding treatmentde-escalation, the ‘value’ of expensive new drugsin relation to their standard counterparts, andoptimal radiotherapy techniques in the cura-tive setting have received answers that willundoubtedly affect clinical practice.

A popular and relatively low-risk path foranticancer drug development consists of addingnew agents to the ‘standard of care’. As a result,we have witnessed an escalation in drug pre-scription, with an exponential rise in drug costs.Withholding some of the most toxic compo-nents of new standard-of-care treatments incarefully selected patients with breast cancer

is an important but difficult task for academicinvestigators to undertake, but this approachhas been successful in other diseases, mostlyin paediatric malignancies. An example comesfrom a single-arm phase II trial from theDana–Farber Cancer Institute, which exploredwithdrawal of anthracyclines from the adju-

vant chemotherapy backbone for low-stage,HER2-positive breast cancer in patients withmostly T1–T2 and node-negative disease1. Thedecision to withdraw anthracyclines to developa less-aggressive standard of care is supportedby the extremely low rate of distant disease

women with a ‘low-risk’ Oncotype DX® scoreand showed that following adjuvant endocrinetherapy, 98.7% of these women remain freefrom recurrence at any site3, highlighting thatchemotherapy can be avoided in these patientswith no detriment to outcome.

Adjuvant trials that aim to optimize radio-therapy fields, doses, or schedules are courage-ous endeavours, as they are notoriously difficultto fund and require large numbers of patientsand very long follow-up times. Two such trialswith mature 10-year follow up were published,and provided consistent results despite differ-ences in study size and patient selection: the

addition of regional nodal irradiation to whole-breast or thoracic-wall radiotherapy does notimprove overall survival, but does reduce therate of local and distant breast cancer recur-rence4,5. The magnitude of this treatment effectis modest and additional translational researchefforts are needed to identify ‘biological’subgroups with enhanced benefit.

mBC is the setting in which all new drugsmust pass the first hurdle in demonstrat-ing efficacy, which is usually established inrandomized phase II–III trials in comparisonwith the standards of care. Not surprisingly,the clinical research landscape is dominated byindustry-led trials. In this regard, the CALGBand NCCTG should be congratulated for theirhead-to-head comparisons of nab-paclitaxeland ixabepilone versus paclitaxel in a first-linechemotherapy trial in 799 patients with mBC.

recurrence observed at a median follow-up ofnearly 4 years following 3 months of weeklypaclitaxel and 1 year of trastuzumab1.

Results of recent clinical trials are nowchallenging the dogma that superior drugregimens in advanced-stage breast cancertranslate into more-efficacious adjuvant thera-pies in the early disease setting. Because ovariansuppression combined with tamoxifen treat-ment was associated with superior outcomesin metastatic breast cancer (mBC), manyclinicians were tempted to generalize its use inadjuvant endocrine therapy for young womenwith luminal disease. The SOFT trial2 has beenimportant in refuting this generalization, asthe benefit of adding ovarian suppression totamoxifen (which is associated with increasedrates of grade 3 or higher adverse events) isrestricted to women who were at sufficientrisk of recurrence to warrant adjuvant chemo-therapy. Of note, the SOFT trial only includedpatients who remained premenopausal afterneoadjuvant chemotherapy 2.

TAILORx is a very large prospective, aca-

demic, US-based trial designed to refineadjuvant chemotherapy withdrawal using theresults of Oncotype DX® — a prognostic andpredictive gene-expression signature alreadyendorsed by many oncologists3. The pri-mary question of the trial pertains to womenharbouring node-negative tumours with an‘intermediate risk’ based on Oncotype DX® score, in whom the benefit of the addition ofadjuvant chemotherapy to endocrine therapyis being investigated; results for this cohortare not currently available. In 2015, however,the trial reported the excellent outcome of

B R E A S T C A N C E R I N 2 0 1 5

Academic research sheds light on issuesthat matter to patients

Martine J. Piccart and Isabelle Gingras

In 2015, academic-led trials provided evidence for safe de-escalation of

adjuvant treatment in early stage breast cancer and answered important

questions related to adjuvant regional irradiation and optimal first-line

chemotherapy in advanced-stage disease. Furthermore, the development

of novel therapies and potential tools for treatment tailoring will offer newhope to patients with breast cancer.

S .B r a d b r o ok / N P G

KEY ADVANCES IN MEDICINE JA NUARY 20 16 | 12

CLINICAL ONCOLOGY


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The winner in terms of progression-free survival (PFS) and time-to-treatment failure wasthe relatively cheap drug paclitaxel6.

Similarly, our colleagues in the UK can beproud of their practice-changing trial7 of up-front carboplatin (AUC x 6 once every 3 weeks)

versus docetaxel (100 mg/m2 every 3 weeks) inwomen with metastatic triple-negative breastcancer (TNBC): a superior response rate for thealkylating agent over the taxane was demon-strated in 43 patients with BRCA-mutatedtumours, representing around 8% of the trialpopulation. When receiving carboplatin,patients with BRCA-mutated tumours hada median PFS of 6.8 months compared with3.1 months in BRCA-wild-type patients7. Fullpublication of this important trial is pending.

Following over two decades of intensivebasic research effort to dissect the molecularmechanisms of endocrine resistance in breastcancer, we can celebrate the rewards of the suc-

cessful registration of new targeted compoundsthat delayed the onset of treatment resistance inpatients with mBC. Letrozole combined withthe CDK4/6 inhibitor palbociclib receivedconditional accelerated approval by the FDAas the first-line endocrine-based therapy formBC, on the basis of extended PFS results ina randomized phase II trial8; palbociclib alsoimproved PFS by 5 months in combinationwith fulvestrant in a phase III trial involving 521patients with relapsed or progressive diseaseduring prior endocrine therapy 9. Palbociclibis associated with a manageable toxicity profile(neutropenia and fatigue), and maintenance ofglobal quality of life9. Whether palbociclib willprovide better survival outcomes than evero-limus remains unknown. Of note, no bio-markers for either of these compounds havebeen validated, beyond the oestrogen receptor,which is a serious problem in view of the steeprises in drug prescription costs.

A huge unmet medical need remains forwomen with metastatic TNBC, as this diseaseusually progresses rapidly following three to

five lines of chemotherapy; to date, no targeteddrug has been registered in this setting, apartfrom bevacizumab, the clinical value of whichhas been questioned because no overall sur-

vival gain could be demonstrated. Considerableinterest has been generated by the encouragingresults obtained with the immune-checkpointinhibitors pembrolizumab and atezolizumab inheavily pretreated women with advanced-stage TNBC. The overall response rate to theseagents remains modest (~18%), but the medianduration of response had not been reached atthe time of publication, indicating sustainedresponses rarely observed in patients withheavily pretreated TNBC10–12. Combinationsof immunotherapies with selected cytotoxicagents or signal-transduction inhibitors willundoubtedly become the focus of intenseclinical investigations in the coming years.

The association of dense stromal tumourinfiltrating lymphocytes (TILs) with

improved outcomes for certain breast can-cer subtypes has long been recognized bypathologists. In the NeoALTTO trial13, thedemonstration of a strong prognostic value ofTILs for both pathological complete responseand event-free survival (independent of ther-apy) in patients with HER2-positive disease,could lead to an ‘actionable biomarker’ fortreatment de-escalation, if validated in the

very large ALTTO adjuvant trial.Finally, 2015 will be remembered for the

powerful demonstration of molecular imagingto decipher the considerable tumour hetero-geneity in advanced-stage HER2-positive breastcancer. The academic-led ZEPHIR trial, inwhich 56 patients with HER2-positive diseaseunderwent a HER2 PET–CT assessment beforereceiving T-DM1, revealed that almost half ofthe patients had substantial heterogeneity inHER2 expression between different meta-stases14. Moreover, 29% of the patients had anegative HER2 PET–CT; importantly, patientswith a negative HER2 PET–CT scan showedmarginal benefit from T-DM1 therapy 14. The

consequences of these findings are potentiallysubstantial with respect to improving ourability to identify who might benefit from thisanti-HER2 antibody drug conjugate.

Martine J. Piccart is at the Department of Medical

Oncology, Institut Jules Bordet/Université libre de

Bruxelles, 1 Rue Héger-Bordet, 1000 Bruxelles,

Brussels, Belgium.

Isabelle Gingras is at the Department of Hematology

and Oncology, Hôpital du Sacré-Cœur de Montréal/

Université de Montréal, 5400 Boulevard Gouin,

Montreal, Quebec H4J 1C5, Canada.

Correspondence to M.J.P.

[email protected]

doi:10.1038/nrclinonc.2015.236


1. Tolaney, S. M. et al. Adjuvant paclitaxel and

trastuzumab for node-negative, HER2-positive breast

cancer. N. Engl. J. Med. 372, 134–141 (2015).

2. Francis, P. A. et al. Adjuvant ovarian suppression in

premenopausal breast cancer. N. Engl. J. Med. 372,

436–446 (2015).

3. Sparano, J. A. et al. Prospective validation of a 21-gene

expression assay in breast cancer. N. Engl. J. Med. 373,2005–2014 (2015).

4. Whelan, T. J. et al. Regional nodal irradiation in early-

stage breast cancer. N. Engl. J. Med. 373, 307–316

(2015).

5. Poortmans, P. M. et al. Internal mammary and

medial supraclavicular irradiation in breast cancer.

N. Engl. J. Med. 373, 317–327 (2015).

6. Rugo, H. S. et al. Randomized phase III trial of paclitaxel

once per week compared with nanoparticle albumin-

bound nab-paclitaxel once per week or ixabepilone

with bevacizumab as first-line chemotherapy for

locally recurrent or metastatic breast cancer:

CALGB 40502/NCCTG N063H (Alliance). J. Clin. Oncol.

http://dx.doi.org/10.1200/jco.2014.59.5298 (2015).

7. Tutt, A. et al. Abstract S3-01: The TNT trial: a randomized

phase III trial of carboplatin (C) compared with docetaxel

(D) for patients with metastatic or recurrent locally

advanced triple negative or BRCA1/2 breast cancer

(CRUK/07/012).Cancer Res. 75, S3-01 (2015).

8. Finn, R. S. et al. The cyclin-dependent kinase 4/6

inhibitor palbociclib in combination with letrozole versus

letrozole alone as first-line treatment of oestrogen

receptor-positive, HER2-negative, advanced breast

cancer (PALOMA-1/TRIO-18): a randomised phase 2

study. Lancet Oncol. 16, 25–35 (2015).

9. Turner, N. C. et al. Palbociclib in hormone-receptor-

positive advanced breast cancer. N. Engl. J. Med. 373,

209–219 (2015).

10. Emens, L. A. et al. Inhibition of PD-L1 by MPDL3280A

leads to clinical activity in patients with metastatic triple-

negative breast cancer. [abstract PD1-6], Presented at

the San Antonio Breast Cancer Symposium (2014).11. Nanda, R. et al. A phase Ib study of pembrolizumab

(MK-3475) in patients with advanced triple-negative

breast cancer. [abstract S1-09], Presented at the San

Antonio Breast Cancer Symposium (2014).

12. Dirix, L. Y. et al. Avelumab (MSB0010718C), an

anti-PD-L1 antibody, in patients with locally advanced

or metastatic breast cancer: a phase Ib JAVELIN solid

tumor trial. [abstract S1-04], Presented at the San

Antonio Breast Cancer Symposium (2015).13. Salgado, R. et al. Tumor-infiltrating lymphocytes and

associations with pathological complete response and

event-free survival in HER2-positive early-stage

breast cancer treated with lapatinib and trastuzumab:

a secondary analysis of the NeoALTTO trial.

JAMA Oncol. 1, 448–454 (2015).

14. Gebhart, G. et al. Molecular imaging as a tool to

investigate heterogeneity of advanced HER2-positive

breast cancer and to predict patient outcome under

trastuzumab emtansine (T-DM1): the ZEPHIR Trial.

Ann. Oncol. http://dx.doi.org/10.1093/annonc/mdv577

(2015).

Competing interests statementM.J.P. declares she is a consultant for and receives honoraria

from AstraZeneca, Invivis, MSD, Novartis, Pfizer, Radius,

Roche-Genentech and Synthon. I.G. declares no competing

interests.

Key advances

• The excellent disease-free survival observed with adjuvant paclitaxel and trastuzumab withoutanthracyclines have set a new standard of care for the adjuvant treatment of small (T1–T2),

node-negative, HER2-positive breast cancer, and highlighted the possibility to de-escalate

treatment for low-risk, early stage, HER2-positive disease1.

• The very low incidence of breast-cancer recurrence observed in node-negative patients

with a ‘low risk’ Oncotype DX® score confirms that these patients should be spared

adjuvant chemotherapy3.

• New data suggest that carboplatin can improve progression-free survival in patients with

BRCA-mutated tumours when used as first-line therapy for metastatic disease7.

• In 2015, two studies demonstrated that palbocilib can improve progression-free survival

of patients with metastatic disease in both the first-line8 and second-line9 settings, and

palbociclib in combination with letrozole received conditional FDA approval for the first-line

treatment of oestrogen-receptor-positive, HER2-negative metastatic breast cancer.


C L I N I C A L O N C O L O G Y

mailto:martine.piccart%40bordet.be?subject=http://dx.doi.org/10.1038/nrclinonc.2015.236http://dx.doi.org/10.1200/jco.2014.59.5298http://cancerres.aacrjournals.org/content/75/9_Supplement/PD1-6?cited-by=yes&legid=canres;75/9_Supplement/PD1-6http://cancerres.aacrjournals.org/content/75/9_Supplement/PD1-6?cited-by=yes&legid=canres;75/9_Supplement/PD1-6http://cancerres.aacrjournals.org/content/75/9_Supplement/PD1-6?cited-by=yes&legid=canres;75/9_Supplement/PD1-6http://cancerres.aacrjournals.org/content/75/9_Supplement/S1-09http://cancerres.aacrjournals.org/content/75/9_Supplement/S1-09http://www.abstracts2view.com/sabcs15/view.php?nu=SABCS15L_984http://www.abstracts2view.com/sabcs15/view.php?nu=SABCS15L_984http://dx.doi.org/10.1093/annonc/mdv577http://dx.doi.org/10.1093/annonc/mdv577http://www.abstracts2view.com/sabcs15/view.php?nu=SABCS15L_984http://www.abstracts2view.com/sabcs15/view.php?nu=SABCS15L_984http://cancerres.aacrjournals.org/content/75/9_Supplement/S1-09http://cancerres.aacrjournals.org/content/75/9_Supplement/S1-09http://cancerres.aacrjournals.org/content/75/9_Supplement/PD1-6?cited-by=yes&legid=canres;75/9_Supplement/PD1-6http://cancerres.aacrjournals.org/content/75/9_Supplement/PD1-6?cited-by=yes&legid=canres;75/9_Supplement/PD1-6http://dx.doi.org/10.1200/jco.2014.59.5298http://dx.doi.org/10.1038/nrclinonc.2015.236mailto:martine.piccart%40bordet.be?subject=


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COLORECTAL AND GASTRIC CANCER IN 2015

The development of new agentsand molecular classifications

Eric Van Cutsem and Michel Ducreux

In a little over the past year, several clinical trials have evaluated new drugs in

patients with metastatic colorectal cancer and gastric cancer. Furthermore,

genomics studies that attempted to unravel the molecular characteristics of

colorectal and gastric cancer were published in 2015. The results of these

endeavours will influence clinical practice in 2016 and beyond.

The median survival of patients with meta-static colorectal cancer (mCRC) has improvedover the past 15 years: in contemporary trials

median survival durations of approximately30 months have been reported1. Several newdrugs have contributed to this advance; how-ever, an unmet need for new agents with agreater clinical effect, which can break thiswall of 30 months, remains. By contrast, themedian survival of patients with metastaticgastric cancer (mGC) remains poor and,generally, does not exceed 12 months. Overthe past year, encouraging data on three newtreatments for mCRC and a new targetedtherapy for mGC have been presented. Inaddition, new genetic classifications havebeen proposed that might help to furtheradvance personalized molecular medicinefor these diseases.

One of the agents that have shown prom-ise in the treatment of mCRC is TAS-102(Taiho Oncology, Japan), which is a combi-nation drug comprising the active cytotoxiccompound trifluridine, a thymidine-basednucleic-acid analogue, and tipiracil hydro-chloride. The triphosphate form of trifluri-dine is incorporated directly into DNA whilethe monophosphate form inhibits thymidy-late synthase, with both of these activitiesultimately resulting in DNA damage and,thus, antitumour effects; tipiracil is a potentinhibitor of thymidine phosphorylase and,

when delivered as part of TAS-102, preventsthe rapid degradation of trifluridine. In thephase III RECOURSE study 2, patients with

chemorefractory mCRC were randomlyassigned to receive best supportive care pluseither TAS-102 or placebo. The median over-all survival improved to 7.1 months withTAS-102, from 5.3 months with placebo (haz-ard ratio (HR) for death 0.68, 95% confidenceinterval (CI) 0.58–0.81; P


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tumours that demonstrate microsatelliteinstability (MSI) — are more responsive toPD-1 blockade than MMR-proficient — ormicrosatellite-stable — tumours7. In particu-lar, immune-related objective responses and20-week immune-related progression-free sur-

vival (PFS) were achieved in four of 10 patients(40%) and seven of nine patients (78%) withMMR-deficient mCRC, respectively, comparedwith none of 18 patients (0%) and two of 18patients (11%) with MMR-proficient mCRC7.Furthermore, excellent survival outcomeswere observed in patients with MMR-deficientmCRC: both median PFS and overall survivalwere not reached after a median follow-upduration of 36 months in this group, but wereonly 2.2 months and 5 months, respectively,in patients with MMR-proficient mCRC7.MMR-deficiency occurs in many cancers,and in patients with CRC, it can arise from aninherited germ-line genetic defect, in the con-

text of Lynch syndrome (hereditary nonpoly-posis colorectal cancer), or it can be sporadic.In either case, the resulting neoplasms harbourhundreds or thousands of mutations, and areconsidered as hypermutated and, therefore,highly immunogenic lesions7.

With regard to mGC, active first-line andsecond-line treatment options remain a majorunmet clinical need. Until now, trastuzumabwas the only targeted agent with clinically-relevant activity in patients with gastric cancer.Early results with anti-VEGFR2 monoclonalantibody ramucirumab indicated that mono-therapy with this agent significantly prolongsthe survival of previously treated patients withmGC, although the magnitude of the benefitremains limited (median overall survival of5.2 months versus 3.8 months with placebo)8.More-recent data indicate, however, that thecombination of ramucirumab with paclitaxelimproves overall survival and could, therefore,be regarded as a new standard second-line

treatment for patients with mGC9. Specifically,in a phase III study 9 published late in 2014,the overall survival of patients treated withramucirumab plus paclitaxel was significantlylonger than that of patients who received pla-cebo plus paclitaxel (median 9.6 months versus 7.4 months; HR 0.807, 95% CI 0.678–0.962;P = 0.017); moreover, ramucirumab therapywas associated with only a modest increasein toxicity 9.

Another key development in late 2014was the publication of The Cancer GenomeAtlas (TCGA) molecular classification thatdivides gastric adenocarcinomas into foursubtypes: Epstein–Barr virus (EBV)-infectedtumours; MSI tumours; genomically sta-ble tumours; and chromosomally unstabletumours10. The EBV-positive tumours displayrecurrent PIK3CA mutations, extreme DNAhypermethylation, and amplification of thegenes encoding JAK2, PD-L1, and PD-L2. MSI

tumours have a high frequency of mutationscompared with the other subtypes, includingmutations in genes encoding targetable onco-proteins10. Genomically stable tumours areenriched for the diffuse histological variantand mutations in RhoA or fusions involvingRho-family GTPase-activating proteins10.Finally, tumours with chromosomal insta-bility, demonstrate marked aneuploidy andfocal amplification of receptor tyrosine kinasegenes10. Identification of these subtypes pro-

vides a roadmap for patient strat ificationand trials of targeted therapies, which mightcontribute to further improving outcomes ofthis disease.

Similarly, in 2015, an international consor-tium has proposed a gene-expression-basedsubtyping classification system for CRC thatdefines four consensus molecular subtypes(CMSs) of CRC with distinguishing features11:CMS1 (MSI–immune, 14%), demonstratinghypermutation, MSI, and strong immune

activation; CMS2 (canonical, 37%), epithelialtumours with marked activation of WNT andMYC signalling; CMS3 (metabolic, 13%), epi-thelial tumours with evident metabolic dys-regulation; and CMS4 (mesenchymal, 23%),with prominent activation of TGFβ signalling,stromal invasion, and angiogenesis. As in thesetting of gastric cancer, this classification willprobably facilitate future CRC research and,together with the ongoing development of thetherapies that have shown promise in 2015,might further improve patient outcomes.

Eric Van Cutsem is at the Digestive Oncology,

University Hospitals Leuven and KU Leuven,

Herestraat 49, 3000 Leuven, Belgium.

Michel Ducreux is at the Gastrointestinal Unit,

Department of Medicine, Gustave Roussy, 114 Rue

Edouard Vaillant, 94805 Villejuif Cedex, France, and

the Faculty of Medicine, Paris Sud University, 63 Rue

Gabriel Péri, 94270 Le Kremlin Bicêtre, France.

Correspondence to E.V.C.

eric.vancutsem@uzleuven.

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