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Professor Joe Duffy is PrincipalGrade Biochemist at St Vincent’sUniversity Hospital, Dublin, andAdjunct Professor in the School ofMedicine and Medical Science atUniversity College Dublin. The mainfocus of Professor Duffy’s researchis novel molecular biomarkers inbreast cancer. For his work,Professor Duffy has received severalnational and international awards.These include the St Luke’s MedalLecture and The Conway ReviewMedal Lecture of the RoyalAcademy of Medicine in Ireland andthe National Biochemistry AwardMedal Lecture of the Royal IrishAcademy. Professor Duffy is amember of a number ofInternational Expert Panels for thepreparation of guidelines on theclinical use of tumour markers,including the European Group onTumour Markers (EGTM) and theNational Academy of ClinicalBiochemistry (NACB). He is currentlyChairman of the NACB Panel forguidelines on the use of biomarkersin breast cancer. Professor Duffyobtained his BSc Hons inbiochemistry from the NationalUniversity of Ireland, Galway, andhis PhD from the University ofManchester.

a report by

J o e D u f f y

Principal Grade Biochemist, St Vincent’s University Hospital Dublin and Adjunct Professor,

School of Medicine and Medical Science, University College Dublin

Although the worldwide incidence of breast canceris increasing, death from this disease is nowdeclining in a number of Western countries.2 Thisdecrease in mortality is likely to result from acombination of mammographic screening andincreased use of systemic adjuvant treatments. Foroptimum care of patients with breast cancer, amultidisciplinary approach is necessary. Thisapproach should involve surgery, histopathology,medical oncology, radiotherapy, radiology and theuse of tumour markers.

Tumour markers are substances that can bemeasured in blood, tumour tissue or other bodyfluid and that aid cancer detection and/ormanagement. Tumour markers are potentiallyuseful in screening for early cancer (e.g. prostate-specific antigen (PSA) in prostate cancer), aidingdiagnosis (tumour markers almost never replacehistopathology for the primary diagnosis ofcancer), determining prognosis, predicting likelyresponse or resistance to therapy, post-operativesurveillance and monitoring therapy in patientswith advanced cancer.

For breast cancer, the existing markers are of littlevalue for screening or aiding early diagnosis. Incontrast, markers are available for determiningprognosis, predicting likely response to therapy,post-operative follow-up and monitoring therapy inmetastatic disease. Prognostic and predictive markeruse is usually determined on tumour tissue whereassurveillance and monitoring markers are measuredin blood. The aim of this article is to review the roleof both tissue and serum markers in the care ofpatients with breast cancer.

T i s s u e Ma r k e r s

H o r m o n e R e c e p t o r s

Hormone receptors (i.e. oestrogen and progesteronereceptors) are carried out in order to determineendocrine-sensitivity of newly diagnosed breastcancers. For hormone receptor-positive patients,endocrine therapy should be administered, i.e.

tamoxifen and/or an aromatase inhibitor forpostmenopausal patients and tamoxifen and/orovarian suppression/ablation for premenopausalpatients. Hormone receptor-negative tumoursshould not be treated with endocrine therapy but arecandidates for treatment with adjuvantchemotherapy. It is generally recommended thatboth oestrogen and progesterone receptors bemeasured together as patients derive maximumbenefit from hormone therapy when both receptorsare present.

While the primary use of hormone receptors is forselecting for endocrine sensitivity, oestrogenreceptors may also be used to determine prognosis.Generally, for the first five years followingdiagnosis, receptor-positive patients have a betteroutcome than receptor-negative patients.However, as a prognostic factor, the impact ofoestrogen receptor is relatively weak, especially inpatients with lymph node-negative disease.Furthermore, the favourable prognostic impact ofhormone receptors disappears after about five yearsof follow-up.

H u m a n E p i d e r m a l G r o w t h F a c t o r

R e c e p t o r - 2

Human epidermal growth factor receptor-2 (HER-2) is primarily measured in order to select patientsfor treatment with Herceptin (trastuzumab).Herceptin is a therapeutic monoclonal antibodydirected against the HER-2 oncoprotein. Whenadministered with chemotherapy to HER-2-positive patients, Herceptin significantly improvedboth progression-free and overall survival in patientswith advanced breast cancer. When given eitherwith or after chemotherapy to patients with HER-2-positive early breast cancer, Herceptin reducedthe risk of recurrence by approximately 50%.

As well as predicting response to Herceptin, HER-2 may be used for determining prognosis in patientswith breast cancer. Generally, patients with HER-2-positive tumours have a worse outcome thanthose with HER-2-negative cancers. Indeed, in the

The C l in i ca l Va lue o f Tumour Markers in Breas t Cancer

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DOI: 10.17925/EOH.2006.0.1.23

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2005 St Gallen Consensus statement, assay ofHER-2 was recommended for classifying risk innewly diagnosed breast cancer patients.

u P A a n d P A I - 1

uPA and PAI-1 are two proteins that promotecancer invasion and metastasis. More than 20independent studies have shown that high levels of uPA or PAI-1 in breast cancer are associatedwith aggressive disease and poor outcome. Most importantly, the prognostic value of these proteins has been validated in the highestavailable level evidence studies, i.e. in level Ievidence studies. These high-level evidence studiesincluded a multicentre randomised prospective trialcarried out in 14 centres in Germany and a pooledanalysis involving data from 18 different centresacross Europe.

Currently, the main clinical use of uPA and PAI-1is for selecting lymph node-negative breast cancerpatients that may not need to undergo treatmentwith adjuvant chemotherapy, i.e. lymph node-negative breast cancer patients with low levels ofuPA and PAI-1 have such a good prognosis thatthe benefit of chemotherapy would be sufficientlysmall that they could avoid the toxic side effectsand high costs of this therapy. On the other hand,patients with high levels of uPA and/or PAI-1 havea poor prognosis (similar to that of patients withthree positive lymph nodes) and thus should betreated with adjuvant chemotherapy.

S e r um Ma r k e r s

The most useful serum markers in breast cancer areCA 15-3 (BR 27.29) and carcinoembryonic antigens(CEAs). As mentioned above, serum markers aremainly used in surveillance following surgicalresection of the primary cancer and monitoringtherapy when patients develop recurrent ormetastatic disease. For both these applications, serialdeterminations of marker(s) are necessary.

P o s t o p e r a t i v e S u r v e i l l a n c e

Approximately 25% of patients with surgically

removed primary breast cancer develop systemicrecurrences and die within five years. Sixty percent to 80% of all recurrences develop within thefirst three years of initial diagnosis. In order todetect recurrent disease at an early stage, patientsare usually followed up at regular intervals. From abiological point of view, it might be expected thatthe early detection of recurrent disease followed bythe initiation of therapy would improve outcomecompared with starting therapy when recurrence isclinically evident.

Serial determinations of markers such as CA 15-3and CEA have the potential to detect recurrentbreast cancer with median lead times of four to fivemonths (occasionally >20 months). It is unclear,however, whether the early detection of recurrentdisease in asymptomatic patients, followed byadministration of therapy, enhances patient

outcome. Indeed, studies carried out over 10 yearsago concluded that intensive follow-up of breastcancer patients did not benefit them comparedwith minimal follow-up. These old studies had anumber of limitations, including:

• use of older and less sensitive biochemical tests, such as alkaline phosphatase, aspartatetransaminase, gamma glutamyl transferase,bilirubin, calcium and creatinne, rather than the newer tumour markers such as CA 15-3 and CEA;

• use of older radiological procedures rather thannewer procedures such as computed tomo-graphy (CT), magnetic resonance imaging(MRI) and positron emission tomography(PET) scanning; and

• most of the reports comparing outcome incontrol and intensively followed-up patientspredate the availability of new treatments forrecurrent/metastatic breast cancer such as thetaxanes, the new generation of aromataseinhibitors and Herceptin.

The relevance of these older studies to the modernmanagement of breast cancer is thus unclear.

For breast cancer, the existing markers are of little value for

screening or aiding early diagnosis.

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According to the European Group on TumourMarker (EGTM) Guidelines, serial CA15-3 andCEA determinations are recommended for the earlydetection of recurrence in asymptomatic patientswho had undergone curative surgery for primarybreast cancer, if the detection of recurrent ormetastatic disease would alter clinical management.Other expert panels such as the American Society ofClinical Oncology (ASCO), however, do notrecommend routine use of tumour markers in thepost-operative surveillance of newly diagnosedbreast cancer patients.

Mon i t o r i n g T h e r a p y i n A d v a n c e dD i s e a s e

Following the commencement of therapy foradvanced disease, it is important to know as quicklyas possible if the patient is responding to thetreatment. If the patient is benefiting, clearly,

treatment should be continued. If, on the other hand,treatment is not effective, an alternative therapy mightbe given. If an alternative therapy is unavailable, thesepatients could be willing to participate in clinical trialsor they could decide to avoid further therapy.

A convenient and relatively inexpensive approach forhelping to establish response is by measuring markerssuch as CA 15-3 or CEA. Generally, decreasingmarker levels correlate with tumour response, whileincreasing markers levels correlate with tumourregression. According to the EGTM guidelines,markers should be measured prior to everychemotherapy course and at least at three-monthlyintervals for patients receiving hormone therapy. TheEGTM defines an increase in marker concentration ofat least 25% to be significant. It is recommended thatsuch an increase be confirmed with a second specimenobtained within a month. If the increase is confirmed,this provides evidence of progressive disease. Similarly,a confirmed decrease in serum levels of more than 50%was stated to be consistent with tumour regression.

In contrast to the EGTM recommendations, theASCO guidelines state that neither CA 15-3 norCEA should be routinely used for monitoringtherapy in patients with advanced breast cancer.

However, this panel also stated that:

“in exceptional circumstances such as the presence ofosseous metastasis, which are difficult to evaluateclinically, the marker level may be able to support theclinical estimate of disease status. However, themarker cannot in any situation stand alone to defineresponse to treatment”.

The European Society of Mastology (EUSOMA) alsorecommends that tumour markers such as CA 15-3 andCEA should not be used in isolation to assess responseor progression if the tumour is assessable by othermeans, e.g. by radiology. However, as with the ASCOguidelines, the EUSOMA guidelines also added that:

“in the absence of evaluable disease, increase intumour marker accompanied by an increase insymptoms (e.g., bone pain) should be taken asindicating disease progression”.

Also, according to these guidelines:

“an increase in serum markers without symptoms ofprogression should prompt a complete work-up toinvestigate for progression of known disease sites orappearance of new sites”.

Con c l u s i o n

It is clear from the above that tumour markers play akey role in the care of patients with breast cancer.Tissue markers such as hormone receptors and HER-2 are now mandatory in determining prognosis andtherapy planning. For post-operative surveillance,serum markers such as CA 15-3 and CEA can be usedto detect recurrent or metastatic disease at an earlystage. These serum makers can also aid the monitoringof therapy in patients undergoing treatment foradvanced disease. Markers are particularly important inmonitoring disease that cannot be evaluated bystandard radiological criteria (e.g. those with irradiatedlesions, pleural effusion, ascites, lytic bone disease andsclerotic bone disease). ■

A version of this article containing references can be foundin the Reference Section on the website supporting thisbriefing (www.touchoncologicaldisease.com).

Approximately 25% of patients with surgically removed

primary breast cancer develop systemic recurrences

and die within five years.

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