HER2 -TARGETED THERAPIES IN BREAST CANCER
A N E D U C AT I O N A L S U P P L E M E N T I N A S S O C I AT I O N W I T HRoche Products Ltd is entirely responsible for theproduction and funding of this promotional educationalsupplement. Roche Products Ltd has identified, briefedand remunerated the authors of this supplementH E R 2-TARG E TED TH ER APIESI N BRE AST CANC E RHOW TO ACH IE VE SYM P TOM CONTROL ,PROLONG ACTIVE TRE ATM E NTAN D OP TIM I S E E N D - OF- LIFE C AREPrescribing Information can be found on pages S26–S32.COPYRIGHT MARK ALLEN GROUP. No other uses without permission.RXUKMBCO00033 July 2017
FOR E WOR DDCONTENTSFOREWORDS3INTRODUCTIONS4elivering multifaceted,quality care to women livingwith metastatic breast cancer(MBC) demands professionalcompetence and an advanced levelof practice. The breast cancernursing community is evolving tomeet this need as more nurses areappointed specifically for theadvanced disease setting, whilenurses who previously worked onlyin early stage disease are nowdelivering care across the diseasetrajectory, fulfilling a ‘diagnosis todeath’ nursing model.The MBC nursing community,linked by UK charity Breast CancerCare and the Roche Nursing Mattersprogramme, offers forums forlearning, and provides ongoingsupport to this group of nurses.This supplement has beencommissioned by Roche ProductsLtd to continue supporting nurseswho treat patients with MBC bysharing learning and best practice,with a view to encouraginginnovation in service delivery.Claire RyanCURRENT TREATMENT OF HER2 METASTATICBREAST CANCERS7Russell BurcombeDEFINING WHAT MATTERS MOST TO PATIENTSS15Tracey ColebyIMPROVING PATIENT CARE: EXPERT NURSINGSERVICE DEVELOPMENTS21Claire RyanABOU T TH E AU THOR SDeclaration of interestRyan C, Burcombe R, Coleby T (2017) HER2-targetedtherapies in breast cancer. Br J Nurs 26(16 Suppl): S1–32 2017 MA HealthcareAll rights reserved. No reproduction, transmission orcopying of this publication is allowed without writtenpermission. No part of this publication may bereproduced, stored in a retrieval system, or transmittedin any form or by any means, mechanical, electronic,photocopying, recording, or otherwise, without theprior written permission of MA Healthcare or inaccordance with the relevant copyright legislation.Published on behalf of Roche Products Ltd by MA Healthcare.Printed by Pensord Press, Blackwood, NP12 2YAPublisher: Andrew IafratiAssociate publisher, medical education and editor: Tracy CowanEditorial project manager and coordinator: Camila FronzoDesigner: Maddy PorterPublished by MA Healthcare Ltd, St Jude’s Church, Dulwich Road,London SE24 0PB, UKTel: 44 (0)20 7501 6732. Email: p.comRXUKMBCO00033 July 2017How to cite this documentAlthough the editor, MA Healthcare and Roche Products Ltd havetaken great care to ensure accuracy, neither MA Healthcare norRoche Products Ltd will be liable for any errors of omission orinaccuracies in this publication.RXUKMBCO00033 July 2017Roche Products Ltd planned and funded the publicationof this supplement. The authors are all independentclinicians who were selected by Roche and they receiveda fee for their contributions.Claire Ryan gained her generalnurse training from UniversityCollege London Hospitals in 1991and completed her cancer nursingtraining in London at The RoyalMarsden. She was appointed to theMacmillan nurse clinician for MBCpartnership post in October 2014.Before that, she was the leadoncology research nurse forMaidstone & Tunbridge Wells NHSTrust. Her clinical focus and researchinterests lie within the portfolio ofclinical trials for MBC.In this newly created partnershiprole with Macmillan, Ryan has beendeveloping new services for womenwith MBC in West Kent. As anadvanced nurse practitioner, she hasdriven forward innovative nurse-ledservices that have bridged primaryand secondary care, resulting in apatient-centred approach forimproving the health and wellbeingof those living with MBC.Russell Burcombe qualified atThe London Hospital and trained inoncology at Mount Vernon CancerCOPYRIGHT MARK ALLEN GROUP. No other uses without permission.Centre and the Middlesex and StBartholomew’s Hospitals beforebecoming a fellow of The RoyalCollege of Radiologists in 1998. Hecompleted an MD researchfellowship in prediction of responseto neoadjuvant chemotherapy forbreast cancer at Mount Vernon’sGray Laboratory in 2001. Thereafter,he sought more experience as aconsultant radiation oncologist inChristchurch, New Zealand, beforebeing appointed consultant clinicaloncologist at the Kent OncologyCentre in 2004.As well as running a clinicalpractice and treating breast and lungcancers, Burcombe takes a specialinterest in providing patient-friendlyinformation. The innovative breastradiotherapy information film hecreated was awarded first prize forbest patient support initiative at the2012 UK Excellence in OncologyAwards. This was followed, in 2014,by a film on chemotherapy, which isnow used widely to educate patientsin Kent and is endorsed by the UKChemotherapy Partnership.He continues to run aprogramme of clinical audit andresearch, with publications in peerreviewed journals and presentationsat national breast and lung cancermeetings.Tracey Coleby has worked withinthe supportive care team at TheChristie in Manchester for more than11 years. During this time, she helda variety of positions alongside herclinical nurse specialist role,including end-of-life project lead anda clinical nurse specialist role withinthe private sector. She has workedclosely with NHS Improvement andthe National Gold StandardsFramework team in innovatingchange. She has a keen interest inbreast oncology, communicationskills training and end-of-life care.For the past 8 years, Coleby hasbeen working closely withconsultants in medical breastoncology to integrate palliative careand collaboratively with patients withadvancing disease. In 2013, this workwon a national award for ‘bestmultidisciplinary team project’.Claire Ryan, Macmillan Nurse ClinicianMetastatic Breast Cancer, Kent OncologyCentre, Maidstone & Tunbridge WellsNHS TrustRussell Burcombe, Consultant ClinicalOncologist, Kent Oncology Centre,Maidstone & Tunbridge Wells NHS TrustTracey Coleby, Macmillan BreastPalliative Care Lead, The Christie NHSFoundation TrustShe is the Macmillan breastpalliative care lead for a 22-monthproject that is building on this workacross the whole breast diseasegroup. She is also undertaking amaster’s in medical ethics andpalliative care on advanced careplanning for patients who are stillundergoing active treatment.BRITISH JOURNAL OF NURSING VOL 26, NO 16 (SUPPL)S3
INTRODUCTIONI NTRODUC TIONS4HER2-targeted therapies“Due to sequential life-prolonging treatmentsand the use of novel drug therapies, manywomen are living with a diagnosis of metastaticbreast cancer and its complications for longer.The complex psychosocial needs of thesepatients can pose a major challenge for healthprofessionals, primary and secondary healthservices, and social care services”Chapter 1 of this supplement exploresoncology treatment approaches and goal setting,as exposure to sequential treatments can extendsurvival for some.The complex psychosocial needs of womenliving with MBC continue to pose a majorchallenge to health professionals, primary andsecondary health services, and social careservices. These issues, which have beenidentified across the care continuum and reflectpolitical, economic and scientific landscapes, arenot unique to the UK. Global internationalsurveys, such as that by Mayer and Grober(2006) and more recently the Global Status ofAdvanced/MBC Decade Report (Pfizer OncologyRXUKMBCO00033 July 2017Claire Ryan Mamillan Nurse Clinician Metastatic Breast Cancer,Kent Oncology Centre, Maidstone & Tunbridge Wells NHS Trust.claireryan4@nhs.netSites of spread, disease biology, performancestatus and patient choice guide oncologymanagement. A significant change in one area ofoncology management is our understanding ofhuman epidermal growth factor receptor 2(HER2)-positive breast cancer, which haschanged from being considered an aggressivedisease with a poor prognosis, to a disease thatcan be treated with anti-HER2 therapy toprolong survival (Verma et al, 2012; Swain et al,2015). An improved understanding of HER2biology and treatment, and the administration ofHER2-targeted drug therapies, can optimise themedical management of HER2-positive MBC.Despite the presence of international consensusguidelines for the management of advancedbreast cancer, which of course should beadhered to (Cardoso et al, 2014), oncologytreatment in the advanced disease settingremains complex, with few proven standards ofcare in MBC overall.RXUKMBCO00033 July 2017Metastatic breast cancer (MBC), alsoknown as secondary breast cancer (SBC),occurs when cells from the primarybreast tumour metastasise from the breast toother parts of the body via the blood orlymphatic systems. The disease may range fromlimited bone metastases to widespread and lifethreatening metastases in visceral organs such asthe liver, lung and brain (National Institute forHealth and Care Excellence (NICE), 2009; 2014).MBC is incurable, and the primary goal oftreatment is to extend life and palliatesymptoms, while preserving quality of life(NICE, 2009; 2014).Sequential life-prolonging treatments andaccess to novel agents as a result of participatingin clinical trials with endpoints that address theburden of MBC have resulted in many patientsliving with a diagnosis of MBC and itscomplications. It is estimated that, in England,almost 500 000 people are living with adiagnosis of breast cancer, but it is not knownhow many have a recurrence or MBC (CancerResearch UK, 2014). It is difficult to gain a trueunderstanding of the scale of the matter, as dataon the number of women diagnosed with MBCare not routinely collected. The continuum ofthe disease is highly variable, with some womenliving for prolonged periods with a good qualityof life, and others experiencing rapid diseaseprogression. Data on the diagnosis of MBC havenot been collected, meaning that the duration ofsurvival and exposure to treatments is unknown(Reed et al, 2010; Breast Cancer Care, 2016).Nevertheless, it is estimated that more than 9500women die of breast cancer every year inEngland (Cancer Research UK, 2014).The median survival from diagnosis of MBCis 2–3 years, although in indolent disease it maybe as long as 10–15 years (Johnston andSwanton, 2006).et al, 2016), show that MBC receives inadequateattention. The Global Status of Advanced/MBCDecade Report analysed key factors that willcontribute to health policy and servicedevelopments for the care and wellbeing ofthose diagnosed and living with MBC.A diagnosis of MBC can be traumatic forpatients, as reflected in increased feelings ofvulnerability, loss of control and uncertainty(Warren, 2010; Schmid-Büchi et al, 2011). Livingwith MBC is a multifaceted and personalexperience that is influenced by a range offactors, many of which are under-researchedcompared with those for early breast cancer(Johnston, 2010; Warren, 2010). Living withuncertainty is an overriding theme in much ofthe literature, which describes experiences ofloss of control and coping with existentialdistress (Nelson, 1996; Warren, 2010). Despitethis, globally, there is a lack of data on supportneeds at particular stages of the diseasecontinuum, as well as inconsistency in thereporting of supportive care for MBC (PfizerOncology et al, 2016).Confusingly, the terms supportive andpalliative care are sometimes usedinterchangeably. Improved training is requiredfor the multidisciplinary health team to definewhat ‘recognition that each patient’s individualtreatment path is unique’ means in practice(NICE, 2012). Palliative care tends to focus onend-of-life care after active cancer therapieshave been withdrawn; however, palliative carehas an equally important role to play during theperiod of living with MBC, as it can focus oneffective management of often distressingsymptoms, incorporating psychosocial care and,ultimately, preparing for end of life.Patients with MBC will inevitably confrontdisease progression, and thus face changingphysical, psychosocial and emotional demands.Understanding these changes will enable experthealth professionals to deliver interventions thatare tailored to meet patients’ holistic needs,thereby resulting in person-centred quality care(Coulter and Collins, 2011; King’s Fund, 2012).At some point in the disease continuum, theaim of treatment will shift from active treatmentto palliative care for symptom management only,with preparation for end of life. Chapter 2examines these changes and attempts to definewhat matters most to patients at different stagesof the disease continuum, offering insight intohow health professionals can be supported indelivering shared care.The vision that everyone affected by MBCshould receive the highest quality care,treatment, information and support highlightsCOPYRIGHT MARK ALLEN GROUP. No other uses without permission.the need for a shift from a one-size-fits-allmedical model approach towards assessment,information, education and person-centred careplans based on individual risks, needs andpreferences. Patients with MBC face increasinglycomplex decisions about their care, as some willlive longer and have more treatment choices.“A diagnosis of metastatic breast cancer canbring increased feelings of vulnerability, loss ofcontrol and uncertainty. Palliative care can havean important role to play at this stage of thedisease continuum as it can be used to manageoften distressing symptoms, providepsychosocial care and, ultimately, preparepatients for the end of life”This shift towards support for selfmanagement might encourage patients withMBC to increase their understanding of what thecancer journey might look like (Fenlon andReed, 2008). However, the cancer journey iscomplex and uncertain, punctuated bychallenges to physical and emotional wellbeing,and inevitable relapses (Reed et al, 2012). Peopleliving with cancer who have access to a clinicalnurse specialist (CNS) are significantly morelikely to be more positive about multiple aspectsof their care and treatment, such as theprovision of information and support(Department of Health (DH) et al, 2010; QualityHealth, 2014; Warren and Mackie, 2014).However, access to support is variable across theUK, and people with MBC have less access tosupport from a CNS at a time when they need itmost (Breast Cancer Care, 2016; Johnston, 2010).Chapter 3 explores the value of the nursingrole within this context, and demonstrates howit can drive service development. It providesevidence of the benefits to patient care,highlighting the advantages of working within acancer community to share practices.In recent years, oncology treatment for MBCin the UK has moved to the ambulatory setting,resulting in less face-to-face time for patientswithin the hospital setting. In response, therehas been a shift to support self-care in parallelwith shared care delivered by healthprofessionals and health organisations withinprimary care (King’s Fund, 2012). However,there are risks that care can become fragmentedand patients exposed to multiple healthproviders. This validates the need for a specialistnurse or key worker to ‘thread together’ care.The literature reports feelings of abandonmentand isolation, and raises concerns about lessBRITISH JOURNAL OF NURSING VOL 26, NO 16 (SUPPL)S5
INTRODUCTIONS6HER2-targeted therapies“A sound relationship between the patient,oncologist and, if accessible, the clinical nursespecialist is needed to facilitate clinical decisionmaking. Patients also need to be involved in thisprocess. To achieve this, they need tounderstand their choices in care decisionsbefore, during illness and at the end of life.Nurses can play a vital role in facilitating this ”CU R R ENT TR E ATM ENT OF H ER 2 M E TAS TATIC B R E AS T C ANCERHI STORIC ALLY, HER 2- POS ITIVE B RE A ST C ANCER HAD A POORPROGNOS I S . THE DE VE LOPM ENT OF MOLECU L AR THER APIES THATTARGE T THE HER 2 RECE P TOR HA S TR AN S FORM E D OUTCOM ES .HE RE , THE E VIDE NCE ON ANTI - HE R 2 THE R APIES I S S U M MARI S E DARXUKMBCO00033 July 2017Breast Cancer Care (2016) Secondary. Not second rate. http://tinyurl.com/ycaxopow (accessed 11 July 2017)Cancer Research UK (2014) Breast cancer incidence (invasive)statistics. http://tinyurl.com/oap7tmc (accessed 11 July2017)Cardoso F, Costa A, Norton L et al (2014) ESO-ESMO 2ndinternational consensus guidelines for advanced breastcancer (ABC2)†. Ann Oncol 25(10): 1871–88. doi: 10.1093/annonc/mdu385Coulter A, Collins A (2011) Making Shared Decision-makinga Reality. No Decision About me, Without me. King’s Fund,London. http://tinyurl.com/ln8tunc (accessed 7 August2017)Department of Health, Macmillan Cancer Support, NHSImprovement (2010) National Cancer Survivorship InitiativeVision. http://tinyurl.com/y8he5kp6 (accessed 7 August2017)Fenlon D, Reed E (2008) What do women with advancedbreast cancer want from their treatment? Advances in BreastCancer: Psychosocial Issues DecemberFilleron T, Bonnetain F, Mancini J et al (2015) Prospectiveconstruction and validation of a prognostic score to identifypatients who benefit from third-line chemotherapy formetastatic breast cancer in terms of overall survival: theMETAL3 study. Contemp Clin Trials 40: 1–8. doi: 10.1016/j.cct.2014.11.005Findlay M, von Minckwitz G, Wardley A (2008) Effective oralchemotherapy for breast cancer. Ann Oncol 19(2): 212–22Johnston SR (2010) Living with secondary breast cancer:coping with an uncertain future with unmet needs.Eur J Cancer Care (Engl) 19(5): 561–63. doi: 10.1111/j.13652354.2010.01216.xJohnston S, Swanton C (2006) Handbook of Metastatic BreastCancer. Informa UKKing’s Fund (2012) Leadership and Engagement forImprovement in the NHS: Together we can. http://tinyurl.com/y7ahdnoy (accessed 11 July 2017)Mayer M, Grober SE (2006) Silent Voices: Women withAdvanced (Metastatic) Breast Cancer Share their Needs andPreferences for Information, Support and Practical Services.https://tinyurl.com/y9udxffd (accessed 11 July 2017)National Cancer Action Team (2010) Excellence in CancerCare: The Contribution of the Clinical Nurse Specialist.https://tinyurl.com/y9ft7g3g (accessed 11 July 2017)National Institute for Health and Care Excellence (2009; 2014)Advanced Breast Cancer: Diagnosis and Treatment. https://tinyurl.com/z3twxhw (accessed 11 July 2017)National Institute for Health and Care Excellence (2012) PatientExperience in Adult NHS Services: Improving the Experienceof Care for People using Adult NHS Services. https://tinyurl.com/j7w2njl (accessed on 7 August 2017)Nelson JP (1996) Struggling to gain meaning: living with theuncertainty of breast cancer. ANS Adv Nurs Sci 18(3): 59–76Pfizer Oncology, European School of Oncology, ABC3 (2016)Global Status of Advanced/Metastatic Breast Cancer:2005–2015 Decade Report. https://tinyurl.com/ybxg57uq(accessed 11 July 2017)Quality Health (2014) National cancer patient experiencesurvey. https://tinyurl.com/y8jyq7u4 (accessed 11 July 2017)Reed E, Scanlon K, Fenlon D (2010) A survey of provisionof breast care nursing for patients with metastatic breastcancer: implications for the role. Eur J Cancer Care (Engl)19(5): 575–80. doi: 10.1111/j.1365-2354.2010.01213.xReed E, Simmonds P, Haviland J, Corner J (2012) Quality of lifeand experience of care in women with metastatic breastcancer: a cross-sectional survey. J Pain Symptom Manage43(4): 747–58. doi: 10.1016/j.jpainsymman.2011.05.005Schmid-Büchi S, van den Borne B, Dassen T, Halfens RJ(2011) Factors associated with psychosocial needs ofclose relatives of women under treatment for breastcancer. J Clin Nurs 20(7–8): 1115–24. doi: 10.1111/j.13652702.2010.03376.xSwain SM, Baselga J, Kim SB et al (2015) Pertuzumab,trastuzumab, and docetaxel in HER2-positive metastaticbreast cancer. N Engl J Med 372(8): 724–34. doi: 10.1056/NEJMoa1413513Verma S, Miles D,
guidelines for the management of advanced breast cancer, which of course should be adhered to (Cardoso et al, 2014), oncology treatment in the advanced disease setting remains complex, with few proven standards of care in MBC overall. “Due to sequential life-prolonging treatments and the use of novel drug therapies, many
for patients with metastatic HER2- positive breast cancer The relative risk of recurrence is decreased by about 50% when HER2 targeted therapy is added to adjuvant cytotoxic chemotherapy in patients with HER2- positive breast cancer Only patients with ER positive breast cancer respond to hormonal manipulation, but the responses are long
ration in the management of metastatic breast cancer (MBC) and as adjuvant therapy in 2005, along with the development and integration of other HER2-targeted therapies, the history and evolution of this breast cancer subtype have changed dramatically [2]. Despite the success of targeted therapies in the treatment of metastatic
pertuzumab, lapatinib and trastuzumab-emtansine. 2.1.1. Trastuzumab Trastuzumab (Herceptin) is a humanised monoclonal antibody binding to the extracellular portion of HER2 close to its transmembrane domain (Fig 1A) (12). It was the first HER2-targeted agent introduced to breast cancer clinics (2) and it remains a key component of the most effective
the field of targeted therapy. Pertuzumab and trastuzumab-emtansine (T‑DM1) have been able to be introduced in HER2-positive breast cancer. Now other anti-HER2 therapies are being developed (e.g. margetuximab, DS-8201a, pyroti-nib) which can overcome other resistance mechanisms in the HER2 signalling pathway. In the field of hormone-receptor-
agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127]. In fact, trastuzumab altered the natural history of patients diagnosed with HER2 BC, both in early and metastatic disease setting, in a major way [8-10]. Nevertheless, there are
4 Breast cancer Breast cancer: A summary of key information Introduction to breast cancer Breast cancer arises from cells in the breast that have grown abnormally and multiplied to form a lump or tumour. The earliest stage of breast cancer is non-invasive disease (Stage 0), which is contained within the ducts or lobules of the breast and has not spread into the healthy breast tissue .
Human epidermal growth factor receptor (HER2) over-ex-pression is present in about 15–20% of breast cancers [ 1]. Until the development of HER2-targeted therapies, this breast cancer subtype was associated with a worse progno-sis [1]. Despite the success of targeted agents, resistan
In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive . Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab joined by a stable linker to the microtubule inhibitor emtansine
