use of trastuzumab in australia and new zealand: results from the national breast cancer audit

Use of trastuzumab in Australia and New Zealand: results from the

National Breast Cancer Auditans_5998 234..239

Robert Whitfield,* James Kollias,* Primali De Silva,† Helen Zorbas§ and Guy Maddern†‡*Department of Breast, Endocrine & Surgical Oncology, Royal Adelaide Hospital, North Terrace†Royal Australasian College of Surgeons, North Adelaide‡Department of Surgery, The University of Adelaide, The Queen Elizabeth Hospital, South Australia and§National Breast and Ovarian Cancer Centre, New South Wales, Australia

Key words

age factor, breast cancer, clinical practice pattern,registry, trastuzumab.

Abbreviations

HER-2, human epidermal growth factor receptor type-2;NBCA, National Breast Cancer Audit; NBOCC, NationalBreast and Ovarian Cancer Centre.

Correspondence

Dr Robert Whitfield, Department of Breast, Endocrine &Surgical Oncology, Royal Adelaide Hospital, NorthTerrace, Adelaide, SA 5000, Australia. Email:[email protected]

R. Whitfield FRACS; J. Kollias MD, FRACS; P. De

Silva PhD, BSc, BCompSci; H. Zorbas MBBS, FASBP,MAICD; G. Maddern FRACS, PhD.

The paper is based on a poster presented at the 2010RACS ASC.

Accepted for publication 17 June 2011.

doi: 10.1111/j.1445-2197.2011.05998.x

Abstract

Background: Trastuzumab increases disease-free and overall survival in HER-2-positive, early breast cancer. In 2007, the National Breast and Ovarian Cancer Centrerecommended that patients with HER-2 positive cancers (node positive or node nega-tive tumours >1 cm) be offered adjuvant trastuzumab with chemotherapy. The aim ofthis study was to evaluate recent trends in trastuzumab therapy in Australia and NewZealand.Methods: Following data were obtained from the National Breast Cancer Audit forpatients treated between 2006 and 2008: tumour size, number of cases recorded persurgeon per year, location of hospital, HER-2 receptor status, age, lymph node status,chemotherapy and trastuzumab treatment.Results: Data were available from 23 290 patients. During the study period, thepercentage of breast cancers tested for HER-2 rose from 77% to 91%. Patients over 70had fewer HER-2 tests than their younger counterparts. Fourteen percent of tumourswere HER-2 positive; the proportion treated with trastuzumab in 2006, 2007 and 2008was 50%, 66% and 74%, respectively. Significantly more node-positive patients (77%)were given trastuzumab than node-negative patients (52%). All the patients prescribedtrastuzumab also received chemotherapy. Patients under 70 years, patients treated inAustralia and patients treated by higher caseload surgeons were more likely to beprescribed trastuzumab than those over 70, patients in New Zealand and patientstreated by lower caseload surgeons.Conclusions: Trastuzumab-prescribing trends conform to the published guidelines.However, older patients and those with HER-2 positive, node-negative tumours >1 cmmay be undertreated in some cases.

Introduction

Breast cancer is the most common cancer in women in Australia,with 12 614 invasive cancers diagnosed in women in 2006. Morethan two thirds (69%) of these cases were in women aged between40 and 69 years.1

HER-2/neu belongs to a family of four transmembrane receptortyrosine kinases that mediate cell growth, differentiation and sur-vival.2,3 In 20–25% of breast cancers, the HER-2/neu protein isoverexpressed, the HER-2/neu gene is amplified, or both areobserved, with the presence of either carrying an adverse progno-sis.4,5 Trastuzumab (Herceptin®; Genentech Inc., South San Fran-

cisco, CA, USA) is a recombinant humanized monoclonal antibodyagainst the human HER-2 receptor that has been shown to increasedisease-free and overall survival in patients with HER-2-positive,early breast cancer compared with adjuvant chemotherapy alone.6–10

In March 2007, the National Breast and Ovarian Cancer Centre(NBOCC) published recommendations for the use of trastuzumab.11

According to the guidelines, patients with early breast cancer andHER-2-positive tumours, either node positive or node negative withtumours larger than 1 cm, should be offered trastuzumab with che-motherapy following surgery. No recommendations were maderegarding patients with HER-2-positive, node-negative tumoursless than 1 cm, due to a lack of evidence. Trastuzumab was not

ORIGINAL ARTICLEANZJSurg.com

© 2012 The AuthorsANZ Journal of Surgery © 2012 Royal Australasian College of SurgeonsANZ J Surg 82 (2012) 234–239

recommended as a single agent therapy, that is, without chemo-therapy, also due to a lack of data. In addition, no specific recom-mendations were made regarding the use of trastuzumab in olderwomen.

The aim of this study was to evaluate trends in the use of trastu-zumab in early breast cancer in Australia and New Zealand since thepublication of the NBOCC guidelines. Of particular interest was thelevel of adherence among clinicians to the recommendations, andwhether any patient subgroups exist in which there is a significantdiscrepancy between treatment and the evidence-based guidelines.

Methods

In this study, we obtained data from the Royal Australasian Collegeof Surgeons – National Breast Cancer Audit (NBCA). The NBCAdatabase is a joint initiative of the Breast Section of the RoyalAustralasian College of Surgeons in conjunction with the AustralianSafety and Efficacy Register of New Interventional Procedures –Surgical that was established in 1998. Surgical and clinical informa-tion regarding patients with breast cancer has been contributed byover 270 surgeons in Australia and New Zealand. Up to December2008, the database held information on over 60 000 breast cancerepisodes. An episode refers to the diagnosis and treatment period ofa patient’s breast cancer. The robust collection of data is used as atool for providing feedback to participants on trends in surgicalpractice and also to develop standards of best practice for breastcancer management.

For this study, data from the NBCA database were analysedregarding all patients treated for invasive breast cancer betweenJanuary 2006 and December 2008. The following data items wereextracted from the dataset for analysis: tumour size, HER-2 receptorstatus, age, lymph node status, number of cases recorded per surgeonper year, location of hospital, chemotherapy treatment and trastu-zumab treatment. Data were available from 23 290 patient episodes.However, lymph node status was not available for some of theserecords. Locations of Australian hospitals were grouped into majorcity, inner regional, outer regional/remote using Australian Geo-graphical Classification system. When calculating the caseload ofthe surgeon, it was assumed that surgeons had entered all of theircases into the NBCA database.

To record HER-2 receptor status as positive in the NBCA data-base, the test must be based on positive results of an in situ hybrid-ization test (e.g. fluorescence in situ hybridization, chromogenic insitu hybridization). Immunohistochemistry is not considered a finalresult for HER-2 status.

The data were analysed using chi-square test. A statistical signifi-cance level of P < 0.001 was used. All statistics were calculatedusing the Statistical Package for Social Sciences software (SPSSInc., Chicago, IL, USA).

Results

Testing for HER-2 receptor status

There was a significant increase in the percentage of patients testedfor HER-2 receptor status over the study period (P < 0.001), from77% to 91% (Table 1). Overall, 14% of tumours tested were HER-2positive.

Trastuzumab treatment of HER-2 positivetumours

The overall proportion of HER-2 positive patients treated withtrastuzumab in 2006, 2007 and 2008 was 50%, 66% and 74%,respectively. Over the 3-year timeframe, 77% of HER-2-positive,node-positive patients were given trastuzumab compared with 52%of HER-2-positive, node-negative patients. Examining the dataspecifically with respect to conformity with the NBOCC recom-mendations, there was a significant increase in the overall percent-age of HER-2 positive patients managed in accordance with theguidelines over the study period (P < 0.001). Compliance with theguidelines increased from 67% to 84% for patients with node-positive tumours and from 40% to 71% for patients with node-negative tumours >1 cm. This observed difference in trastuzumabtherapy favouring patients with node-positive tumours over node-negative tumours >1 cm also reached statistical significance (P <0.001) (Table 1).

Over the study period, the proportion of patients with HER-2-positive, node-negative tumours �1 cm that received trastuzumabalso increased significantly from 16% to 43% (P < 0.001), despitethe fact that there are no current recommendations for the use of thedrug in this group (Table 1).

It appears that all the patients that were given trastuzumab alsoreceived chemotherapy, consistent with the published recommen-dations. Between 2005 and 2008, 34 patients were recorded ashaving been given trastuzumab without chemotherapy. However,surgeons were contacted regarding these patients and all whoresponded indicated that these were in fact data entry errors, thatis, these patients had actually been given trastuzumab with che-motherapy. These records were not included in the analysis inTables 1–4.

Table 1 Number and percentage of patients treated according to the tumour groups

Year Tested TreatedHER-2-positive, node-positive

tumoursHER-2-positive, node-negative

>1 cm tumoursHER-2-positive node-negative

�1 cm tumours

2006 77.3% (6388/8261) 67.4% (238/353) 39.8% (103/259) 15.8% (15/95)2007 86.4% (6285/7277) 79.1% (261/330) 64.1% (184/287) 29.9% (29/97)2008 91.1% (7062/7752) 84.2% (379/450) 71.2% (232/326) 43.2% (57/132)

Trastuzumab use in Australia and New Zealand 235

© 2012 The AuthorsANZ Journal of Surgery © 2012 Royal Australasian College of Surgeons

Trastuzumab treatment of HER-2-negativetumours

The number of HER-2 negative patients recorded as being treatedwith trastuzumab in 2006, 2007 and 2008 was 56, 58 and 53, respec-tively. This represented approximately 1% of all HER-2-negativepatients. Surgeons were contacted regarding the accuracy of theserecords and all who responded (59% of those contacted) reportedthat these were data entry errors, that is, these patients had not beengiven trastuzumab.

Influence of age on testing and treatment

Although the proportion of patients tested for HER-2 receptor statusincreased across all age groups during the study period, overall only81% of patients over 70 were tested compared with 86% under 70(P < 0.001) (Table 2).

When treatment was stratified by age, there were also significantlyfewer patients in the over 70 group that received trastuzumab andchemotherapy in accordance with the recommendations (33%) com-pared with patients under 70 (75%) (P < 0.001). Even in the mostrecent year of the study period, fewer than half of the patients over70 with HER-2-positive, node-positive tumours received trastu-zumab (Table 2).

Influence of location of hospital on testing andtreatment

The proportion of patients tested for HER-2 receptor status andtreated with trastuzumab according to the guidelines increased inhospitals at all locations in Australia and in New Zealand from 2006to 2008 (Table 3).

In 2008, there was no significant difference in the proportion ofpatients tested for HER-2 according to location of the Australianhospital or between Australian and New Zealand hospitals.However, in 2008 only 68% of patients in New Zealand receivedtrastuzumab treatment in accordance with the guidelines, comparedwith 82% of patients in Australia (P < 0.001) (Table 3).

Influence of surgeon caseload on testing andtreatment

The proportion of patients tested for HER-2 receptor status andtreated with trastuzumab according to the guidelines increased forall surgeon caseload groups from 2006 to 2008 (Table 4).

For the period 2005–2008, patient HER-2 status testing did notvary according to surgeon caseload (P = 0.996). However, patients ofsurgeons who treated �20 breast cancers per year were given tras-

tuzumab in accordance with the guidelines only 57% of the time; forpatients of surgeons managing >20 cases per year, this proportionincreased to 70% (Table 4).

Discussion

This study shows that among Australian and New Zealand surgeonscontributing to the NBCA, there have been clear trends both towardsincreased testing of early breast cancer specimens for HER-2 recep-tor status, as well as increased treatment of HER-2 positive patientswith trastuzumab, between 2006 and 2008. These have occurred inthe setting of the publication of specific treatment recommendationsfor the use of trastuzumab by the NBOCC in early 2007.11 Thegreater use of trastuzumab in HER-2-positive patients has largelyconformed to the NBOCC guidelines, although there remain severalareas in which current practice deviates from the recommendationswithout a sufficient evidence base to justify the discrepancy.

The increased testing of early breast cancer pathological speci-mens for HER-2 receptor status to 91% over the duration of thestudy likely reflects an increasing awareness among pathologists,medical oncologists and surgeons during this period of the potentialutility of trastuzumab as molecular targeted therapy in the adjuvantsetting. In addition, trastuzumab was listed on the Australian Gov-ernment Pharmaceutical Benefits Scheme in October 2006 for thetreatment of HER-2-positive early stage breast cancer, providing asubsidy in the order of $50 000 per eligible patient.12 This decisionfacilitated access to trastuzumab by many women who would haveotherwise been unable to afford it, providing an additional reason forclinicians to request HER-2 receptor testing.

The increased prescription of trastuzumab over the study period isa logical corollary of increased HER-2 testing. By 2008, 84% ofHER-2-positive, node-positive patients were prescribed this medi-cation. The proportion of HER-2-positive, node-negative patientswith tumours over 1 cm that were given trastuzumab also increasedover the study period; however, even in 2008 only 71% of this groupreceived the drug. It would appear that there might have been aperception among clinicians that the relative benefit of trastuzumabwas smaller in node-negative patients. However, this view is notborne out by the evidence. Enrolment in the adjuvant trastuzumabtrials was largely confined to patients considered at high risk ofrecurrence, either lymph node positive or high-risk, lymph nodenegative disease, with few patients with T1a or T1b tumoursincluded in the latter.6–10 None of the trials were sufficiently poweredto examine the relative benefit of trastuzumab within patient sub-groups. Examination of the forest plots of hazard ratios for disease-free survival in three of the trials suggests that all patient subgroups

Table 2 Number and percentage of patients tested and treated for HER-2, by age group

Year Tested HER-2-positive, node-positive or >1 cmtumours treated according to guidelines

<40 years 40–70 years >70 years <40 years 40–70 years >70 years

2006 78.8% (360/457) 78.7% (4833/6143) 71.9% (1195/1661) 74.1% (43/58) 59.0% (281/476) 21.8% (17/78)2007 87.9% (321/365) 87.0% (4647/5342) 83.9% (1317/1570) 81.8% (36/44) 78.5% (376/479) 35.1% (33/94)2008 91.8% (405/441) 92.3% (5315/5761) 86.6% (1342/1550) 85.5% (65/76) 83.6% (508/608) 41.3% (38/92)

236 Whitfield et al.


benefitted equally from trastuzumab, regardless of age, lymph nodestatus, menopausal status or hormone status.13 It is interesting to notethen, that despite apparent relative caution among clinicians to pre-scribe trastuzumab to high-risk node-negative patients, by 2008,43% of patients with low-risk, HER-2-positive, node-negativetumours �1 cm were given the drug, despite a lack of evidence tosupport its use in this group. The likely explanation for this paradoxis due to differences in opinion among clinicians about the utility oftrastuzumab in this setting. Some oncologists would routinely treatmost of these patients, on the basis that several papers have reporteda high risk of relapse in this group.14–16 However, it is unlikely thatfuture trials of adjuvant trastuzumab will be undertaken to defini-tively address its efficacy in this subset of patients. Certainly, thereappears to be room for improvement with regard to better targetingof trastuzumab to patients that are likely to receive the greatestbenefit.

As expected, all patients prescribed trastuzumab also receivedchemotherapy as per the NBOCC guidelines. The stipulation thattrastuzumab is only subsidized when given in combination withchemotherapy is a condition of its Pharmaceutical Benefits Schemelisting.12

The small number of HER-2-negative patients reported as havingbeen given trastuzumab in each study year defies a logical clinical orbiological rationale. The surgeons were contacted regarding theaccuracy of these records and all who responded (59% of thosecontacted) reported that these were in fact data entry errors. There-fore, it appears likely that all the patients who received trastuzumabwere HER-2-positive patients.

The data demonstrate that breast cancer patients over 70 weretreated differently from their younger counterparts with respect toHER-2 testing and trastuzumab therapy. Older patients were lesslikely to have their tumours tested for HER-2, and also less likely tobe given trastuzumab in accordance with the NBOCC recommen-dations. In 2008, 49% of patients over 70 with HER-2-positive,node-positive tumours were given trastuzumab and only 32% withHER-2-positive, node-negative tumours >1 cm were prescribed thetherapy. At present, specific guidelines addressing trastuzumab treat-ment in older patients do not exist. Indeed, the NBOCC recommen-dations state that this is an area in which further research is requiredto determine optimal therapy. The likely explanation for theobserved cautious treatment of older patients in this study is thatclinicians are generally more prudent when contemplating poten-tially toxic systemic therapies in patients who may already havesignificant co-morbid medical conditions. The cardiotoxic adverseeffects of trastuzumab are well recognized, with congestive heartfailure reported in 27% of patients treated concurrently with anthra-cyclines in Slamon et al.’s seminal paper in metastatic disease.17

Severe cardiotoxicity was also observed in the subsequent adjuvanttrials, although at a lower frequency after trastuzumab was not givenconcurrently with anthracyclines in these studies. The percentage ofpatients having to stop trastuzumab treatment because of cardiacissues in the HERA trial,8,18 the PACS-04 trial19 and the NSABP B31trial20 was 4.3%, 17.9% and 15.5%, respectively. Older age has alsobeen reported as a risk factor for increased cardiotoxicity with adju-vant trastuzumab therapy.20,21 The disinclination of clinicians in ourstudy to prescribe trastuzumab and chemotherapy to patients overT

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70, in particular node-negative patients, may indicate that the uncer-tain gain in disease-free and overall survival with the therapy may beexceeded by an increase in treatment-related morbidity in this agegroup. At the present time, there is little evidence either for oragainst the practice of withholding trastuzumab in older patients,and further research is required to determine its safety and efficacyin this setting.

It is interesting to note that fewer patients in New Zealand weregiven trastuzumab in accordance with the NBOCC guidelines thantheir Australian counterparts. This may reflect the fact that publicfunding for trastuzumab treatment was comparatively limited in NewZealand prior to December 2008.22 The data also show that patientswere more likely to be prescribed trastuzumab in accordance with theguidelines if their surgeon treated more than 20 breast cancers peryear. This is consistent with reports of an association between highercaseloads and improved outcomes after breast cancer surgery.23 Itmay be that improved concordance with NBOCC practice guidelinesin higher-volume centres in Australia and New Zealand is related toeasier access to multidisciplinary team care in these centres.However, the availability of such care could not be determined frominterrogation of the NBCA database. Nonetheless it is encouragingthat the recommended trastuzumab treatment increased across allsurgical caseload groups during the study period.

In conclusion, the results of this study show that between 2006and 2008, the management of patients with HER-2-positive earlybreast cancer changed significantly among surgeons contributing tothe NBCA. HER-2 testing and trastuzumab treatment both increasedmarkedly during the study period. Since the publication of theNBOCC evidence-based recommendations for the use of trastu-zumab, clinical practice has increasingly conformed to those bestpractice guidelines. However, the management of node-negativepatients and patients over 70 years of age differs from the recom-mendations in a proportion of patients. Improved adherence to theguidelines in these areas may result in improved patient outcomes inthe future.

Acknowledgements

Participation in the National Breast Cancer Audit (NBCA) by allcontributing surgeons is gratefully acknowledged. The NBCA hasbeen made possible by generous support from a number of bodiessince its inception. During the period covered in this paper, fundingwas mainly derived from the National Breast and Ovarian CancerCentre. Subsequent funding has derived from the Breast Surgeons’Society of Australia and New Zealand (Breast SurgANZ).

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Table 4 Number and percentage of patients tested and treated for HER-2, by caseload of the surgeon

Year Tested HER-2-positive, node-positive or >1 cmtumours treated according to guidelines

1–20 >20 1–20 >20

2006 79.9% (386/483) 77.1% (6002/7778) 39.4% (13/33) 56.6% (328/579)2007 85.9% (352/410) 86.4% (5933/6867) 56.3% (18/32) 73.0% (427/585)2008 89.4% (356/398) 91.2% (6706/7354) 72.1% (31/43) 79.1% (580/733)

238 Whitfield et al.


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use of trastuzumab in australia and new zealand: results from the national breast cancer audit

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