The Breast (2006) 15(S2) S3–S10

www.elsevier.com/locate/breast

The preferred treatment for young womenwith breast cancer – mastectomy versusbreast conservation1

J.G.H. van Nes, C.J.H. van de Velde*

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands

KEYWORDSBreast cancer;Young women;Mastectomy;Breast-conserving

surgery;Breast-conserving

therapy

Summary Paradigms on breast cancer influence surgical treatment policies.Randomised trials that compared mastectomy with breast-conserving therapy (BCT)with adequate radiotherapy showed no difference in overall survival. However, aftera long follow-up, BCT was associated with a higher local recurrence rate (up to fourtimes higher). The EBCTCG meta-analysis of 2005 concluded that one breast cancerdeath can be avoided for four local recurrences avoided. A minority of breast cancerpatients are younger than 40 years (6.5%). When confronted with the diagnosis ofbreast cancer, they potentially have a long lifespan. Therefore, it is crucial to avoidlocal recurrences. The following factors have a positive impact on local control:mastectomy (in stead of BCT), negative surgical margins and adjuvant treatment(radiotherapy and chemotherapy). In order to provide optimal local and systemictreatment for young patients, breast cancer requires a multidisciplinary approachand the patient has to be involved in the proper treatment decision. A predictivemodel is needed for doctors and patients to facilitate this process.© 2006 Elsevier Ltd. All rights reserved.

IntroductionIntuitively, minimal mutilation is preferred whentreating young patients with breast cancer. Asmall minority of breast cancer patients are youngwomen; 6.5% are younger than 40 years. Unfor-tunately, young women are underrepresented inclinical trials and this population is not separatelyanalysed. Trials specifically focussing on youngwomen are lacking.

* Corresponding author. Prof.dr. C.J.H. van de Velde,FRCS (London), FRCPS (Glasgow). Department ofSurgery, K6-R, Leiden University Medical Center,P.O. Box 9600, 2300 RC Leiden, The Netherlands.Tel.: +31 71 5262309; fax: +31 71 5266750. E-mail:c.j.h.van_de_velde@lumc.nl (C.J.H. van de Velde).

Trials comparing mastectomy and breast-conserving therapy (BCT), as well as theEarly Breast Cancer Trialists’ Collaborative Group(EBCTCG) meta-analysis of 1995, found no dif-ferences in overall and relapse-free survivalbetween the two treatment arms. However, aftera longer follow-up, concerns about local controlarose leading to discussion. Generally, the chanceof a local recurrence is 1% per year afterBCT. Young patients have a longer lifespan thanolder patients. This means longer exposure tothe chance of local or distant recurrences. Forexample, if a patient was 30 when treated forbreast cancer with BCT, the local recurrence riskwill be 50% when she is 80. However, the question

1 This article is based on the presentation given at the ESO advanced course “Breast Cancer in Young Women”.

0960-9776/$ - see front matter © 2006 Elsevier Ltd. All rights reserved.

S4 J.G.H. van Nes, C.J.H. van de Velde

is whether younger patients are at the same risk asolder patients. Is their chance of local recurrencealso 1% a year? And if not, what is acceptable? Isthere an influence on survival or local recurrencerate? We feel that mastectomy as an alternativetreatment option in patients eligible for BCT has tobe considered and discussed in every single youngpatient with breast cancer.

After reviewing the history of surgical treatmentof breast cancer, the focus will be on factorsimportant for local control. Finally, psychologicaland cosmetic aspects will be discussed.

From radical to cosmetically acceptedsurgery

The history of breast cancer treatment is a longand interesting one. Surgery is the oldest methodand different operations reflected differentphilosophies about the cause and natural historyof breast cancer. William Stewart Halsted, chiefsurgeon at the Johns Hopkins Hospital from 1890 to1922, introduced the radical mastectomy at a timewhen local control was the main problem 1. Thisincluded en bloc removal of the breast (tumourand breast tissue), muscles (musculus pectoralismajor and minor) and the axillary lymph nodes.Halsted’s paradigm, based on William SampsonHandley’s theory, was that breast cancer arosein one location (the breast) and would spreadoutward by direct extension, stressing the need forradical en bloc surgery 2. The Halsted mastectomywould become the standard operation for breastcancer of all stages, regardless of the patient’sage, for more than 80 years. Stephen Paget (1855–1926) was an English surgeon. He was the firstto deduce that cancer cells from the primarytumour spread through the bloodstream to allorgans of the body, but could grow only in certainorgans. The same conclusion was published by theAmerican pathologist James Ewing: cancer cellsspread by circulating in the bloodstream to distantsites. In 1938, Gray published his finding that thedeep fascia is poor in lymphatics and hence notan important potential plane for spread 3. Thisdismissed the en bloc theory of radical surgeryand resulted in less extensive operations (modifiedradical mastectomy) with results as good as thoseof the standard radical operation 4.

Radiology made its entrance at the end ofthe 19th century. X-rays were introduced bythe German physics professor Wilhelm ConradRoentgen. Herman Moritz Gocht was one ofthe first to use radiotherapy for inoperablebreast cancer and postoperative recurrence 5.

During the 20th century, there was a progressiveimprovement in radiotherapy techniques. X-rayswere being used for cancer diagnosis and astreatment for cancer. Robert McWhirter supportedradiotherapy at that time. He published the resultsof nearly 2000 patients who were treated bysimple mastectomy followed by radiotherapy 6.Besides, he suggested that irradiation was acredible alternative to surgery in the managementof axillary metastases.

Sir Geoffrey Keynes (1887–1982), an Englishsurgeon, excised the tumour and inserted radiumneedles. The five-year survival appeared to be asgood as those achieved by radical mastectomy 7.Nevertheless, his technique was not followed untilReginald Murley (1916–1997), an English surgeon,read his records and told this to George CrileJr. (1864–1943), an American surgeon. Crile Jr.was so impressed by the reports of McWhirterand Murley that he performed his last radicalmastectomy in 1954 8. He tried more conservativeapproaches and reported 57 patients treated withwide local excision in 1971 9. He recommended arandomised study to compare wide local excisionand mastectomy 10. In the mid-20th century,more and more surgeons began to questionHalsted’s ideas. New insights suggested that lessradical surgery might be just as effective asthe more extensive operations that were beingperformed 11,12. Important articles were publishedafter the rise of tumour registries and long-termsurvival studies 13-15. Using these registries, itwas demonstrated that less than one-fifth of thepatients appeared to be cured. The publishedstudies of Gray were re-discovered and it wasdemonstrated that tumour cells directly enter thevenous system 16,17. Besides, Fisher and Fisher’swork demonstrated that lymph nodes were poorbarriers to the spread of cancer cells 11. Breastcancer was a systemic disease. Loco-regional anddistant tumour spread were regarded as twoindependent entities. It became clear that largeroperations did not mean fewer recurrences or lessmortality. Therefore, several randomised trialswere set up to compare mastectomy with breast-conserving therapy (BCT).

Mastectomy versus breast-conservingtherapy

Table 1 shows the overall survival percentages andthe local recurrence rates from the randomisedtrials comparing mastectomy with BCT 18-24. TheMilan trial of Umberto Veronesi started in 1973

Preferred treatment for young women with breast cancer – mastectomy vs. breast conservation S5

Table 1Randomised trials comparing mastectomy and breast-conserving therapy (BCT). In all trials, there is no significant differencein overall survival between mastectomy and BCT. In most trials, there is a significant difference in local recurrence ratebetween mastectomy and BCT

Trial Patients >50 years Median FU(years)

OS (%)MST BCT

LRRMST BCT

P valueLRR MST versus BCT

Institut GustaveRoussy 18

179 56% 22 61 52 10/7a 16/2a 0.03/0.90a

NCI 21 237 81% >40 yrs 18 58 54 9 26 NDMilan Cancer Institute 23 701 43% pm 20 59 58 2 9 p < 0.001EORTC 22 868 61% 13 60 55 13 20 p = 0.0097DBCCG 19 905 6 82 79 ND ND NDNSABP B06 20 1851 60% 20 47 46 15 8 ND

a Local recurrence/regional recurrence.Abbreviations: FU, follow-up; OS, overall survival; LRR, local regional recurrence; MST, mastectomy; BCT, breast-conservingtherapy; NCI, National Cancer Institute; ND, no data; EORTC, European Organisation for Research and Treatment ofCancer; DBCCG, Danish Breast Cancer Cooperative Group; NSABP, National Surgical Adjuvant Breast and Bowel Project;pm, postmenopausal; yrs, years.

and 701 patients were included. Patients were ran-domised between radical mastectomy or breast-conserving quadrantectomy in combination withcomplete axillary dissection and postoperativeradiotherapy. With a quadrantectomy operation,one-quarter of the breast is removed. After amedian follow-up of 20 years, no significantdifferences were seen in overall survival betweenthe two treatment arms 23. The same results wereapparent in the American NSABP B06 trial and inthe European EORTC 10801 trial 20,22. The NSABPB06 trial was initiated by Bernard Fisher in 1976.Patients (n = 1851) were randomised betweentotal mastectomy, lumpectomy or lumpectomyfollowed by radiotherapy. Axillary nodes wereremoved regardless of the treatment assigned. Nosignificant differences were observed in disease-free survival, distant disease-free survival oroverall survival among these three groups 20. Inthe EORTC 10801 trial, 868 patients with stage Iand II breast cancer were randomised betweenmodified radical mastectomy versus lumpectomyfollowed by radiotherapy. After a median follow-up of 13.4 years no differences were found withregard to overall survival or in distant metastasis-free rates 22. This was confirmed by the results ofthe meta-analysis from the EBCTCG in 1995 witha median follow-up of 10 years: there were nodifferences in survival between mastectomy andBCT 25. Differences in survival were not evaluatedaccording to age groups.

After ten years of follow-up, a survival differ-ence arose between the two treatment arms in theEORTC 10801 trial. This difference was in favour ofthe patients treated with mastectomy. However,this difference was not significant (p = 0.11).

This difference in locoregional recurrence in thistrial was significant (p = 0.097). The chance of alocoregional recurrence after BCT was 1.6 timeshigher than after a mastectomy (univariate andmultivariate analysis) 22. The same outcomes wereobserved in the Italian trial. Although a largevolume of breast tissue was removed with aquadrantectomy, the probability of recurrencewas four times higher for patients treated withBCT (quadrantectomy) than patients treated withmastectomy. In conclusion, overall survival afterBCT is equivalent to that following mastectomy.However, after a longer follow-up, BCT isassociated with a higher locoregional recurrencerate with no influence on survival in individualtrials.

Local control

Local control depends on several factors. Thesefactors can be divided into three types (Ta-ble 2). Firstly, tumour-related factors like tumoursize and nodal status. Younger patients morefrequently have large tumours, lymph nodeinvolvement and vascular invasion 26-28. Secondly,host-related factors like age and BRCA mutations.BRCA mutations are more common in youngerpatients than in older patients with breast cancer.Although this is a very interesting and specialgroup of breast cancer patients, they will not bediscussed in this paper. Furthermore, new datasuggest that physical activity may also play arole 29. The last type of factors important for localcontrol is treatment-related.

S6 J.G.H. van Nes, C.J.H. van de Velde

Table 2Factors related to local control

Tumour-related Host-related Treatment-related

Tumour sizeNodal statusVascular invasionExtensive in situ component

AgePositive family history BRCA1/2 mutation

SurgeryTypeSkills/experienceMargins

RadiotherapyChemotherapy

Pre-/peri-/postoperative

Age

Breast cancer is not a common condition in youngwomen and several definitions of young patientsare used in the literature. Therefore, it is difficultto define a “young patient” and to compare resultsfrom different trials. Fewer than 2.7% of patientswith breast cancer are younger than 35 years,6.5% younger than 40 years, and 12% youngerthan 45 years. In this article, young patients aredefined as patients younger than 40 years, unlessotherwise indicated. Concerning randomised trialscomparing mastectomy with BCT, most patientsare older than 50 years (Table 1). None ofthese trials analysed the survival and/or localrecurrence rates according to age group. Trialsspecifically comparing BCT and mastectomy inyoung women are also lacking; therefore, we haveto rely on subgroup analyses.

The EORTC trial 22881/10882 (Boost versusno Boost) included 5569 patients with stage Ior II breast cancer. After lumpectomy, axillarydissection and additional radiotherapy patientswere randomised between an additional localiseddose of 16 Gy versus no additional dose 24. Aftera median follow-up of 5.1 years, young patientshad a significantly higher local recurrence ratecompared with older patients. The boost dosereduced the five-year local recurrence rate from20 to 10% in young patients (�40 years).

Type of surgery

Surgery is a very important factor regarding localcontrol and can be divided into three parts; typeof surgery, surgical margins and experience ofthe surgeon. The importance of local control andits effect on survival have been demonstratedby a publication in the New England Journalof Medicine 30. This trial compared locoregionalrecurrence rates in premenopausal high-risk pa-tients. High-risk status was defined as involvementof axillary lymph nodes, a tumour size of morethan 5 cm and/or invasion of the cancer to skin

or pectoral fascia. Patients (n = 1709) receivedmastectomy followed by CMF (cyclophosphamide,methotrexate and fluorouracil) and radiotherapyto the chest wall or chemotherapy (CMF) alone.The median follow-up was almost 10 years. Thefrequency of locoregional recurrence alone or withdistant metastases was 9% among the women whoreceived radiotherapy and chemotherapy and 32%among those who received chemotherapy alone.(p < 0.001). Besides, adjuvant radiotherapy wasassociated with an improved overall survival (54%for CMF and radiotherapy versus 45% for CMFalone) 30. The same results were apparent in an-other randomised Danish trial 31. Postmenopausalwomen (n = 1395) with high-risk breast cancer(stage II or III) received mastectomy followedby tamoxifen and postoperative radiotherapy tothe chest wall and regional lymph nodes oradjuvant tamoxifen alone. The median follow-up was ten years. The locoregional recurrencerate was 8% among the women who receivedradiotherapy and tamoxifen and 35% among thosewho received tamoxifen alone (p < 0.001). Disease-free survival and overall survival were alsomuch higher in those who received tamoxifenalone 31. These trials demonstrated that, evenin the case of inadequate surgery, radiotherapyis capable of decreasing locoregional recurrencerates and improving overall survival. However,a locoregional recurrence rate of 35% aftermastectomy cannot be accepted and radiotherapyshould not be used to compensate for inadequatesurgery.

The EORTC trials 10804, 10854 and 10902,with a total accrual of almost 3000 patients,included almost 1200 young patients (Table 3).The results of multivariate analysis showedthat younger age and breast conservation wereboth independent risk factors for loco-regionalrecurrence 32,33. Patients younger than 35 hada 2.8 times higher risk of local recurrencethan older patients. Patients treated with BCT(all ages) had a 1.8 times higher risk of localrecurrence compared with patients treated with

Preferred treatment for young women with breast cancer – mastectomy vs. breast conservation S7

Table 3The three EORTC trials

EORTC trial 10801 EORTC trial 10854 EORTC trial 10902

Period 1980–1986 1986–1991 1991–1999

Medianfollow-up

13.4 years 10.8 years 6.1 years

Aim Safety of BCT Value of perioperative CT Value of preoperative CT

Design Breast-conserving surgery + radiotherapyversus mastectomy

Perioperative single dose of doxorubicinversus surgery alone

Four cycles of CT (FEC)before or after surgery

Number ofpatients

902 2795 698

Abbreviations: BCT, breast-conserving therapy; CT, chemotherapy; FEC, fluorouracil–epirubicin–cyclophosphamide.

mastectomy. The same results were apparent inthe Institut Gustave Roussy trial, which comparedwide lumpectomy and radiotherapy with modifiedradical mastectomy (n = 179) 18. Young patientstreated with BCT had the highest local recurrencerisk (36% after 15 years). Older patients treatedwith mastectomy had the lowest local recurrencerisk.

Surgical margins

Surgical margins are also important surgicalfactors for local control, which is supportedby two studies. The EORTC trial 10853 was aphase III trial and included almost 1000 patients 34.Patients with DCIS of the breast were randomisedbetween excision with or without radiotherapy.Factors associated with an increased risk of localrecurrence were (among other factors) young ageas well as positive margins (multivariate analysis).Patients with positive margins had a risk oflocal recurrence two times higher than patientswith negative margins. In another study, almost2000 Dutch patients with invasive breast cancerwere analysed 35. All patients were treated withBCT in one single hospital. After a median follow-up of 78 months small significant differences ex-isted in the local recurrence rate between patientswith positive or negative surgical margins. Positivemargins impair local control. However, subgroupanalyses revealed that this was restricted to youngwomen only (again, <40 years). Local recurrencerate at ten years was 58% for young womenwith positive margins (negative margins: 15%)compared with 7% for older women (negativemargins: 6%) 36. This demonstrates that positivemargins may never be accepted in young women!

Surgical experience

Surgical experience is the last discussed part of im-portant surgical factors. In the EORTC trial 10801

(BCT versus mastectomy) it was conspicuous thatthe local recurrence rate differed from hospitalto hospital 22. Differences between hospitals arealso seen in other trials. In Western Australia,patients have better outcomes when treated byhigh caseload surgeons 36. In the UK, differencesin survival rates between consultants were mainlyattributable to the case load (>30 patients peryear) and administration of chemotherapy 37.More administration of chemotherapy was due toinvolvement of multidisciplinary “breast cancerteams”. Breast cancer teams are multidisciplinaryteams involving skilled specialists and nurses 38,39.This team is necessary because of the complexityand multidisciplinary nature of breast cancerdiagnosis and treatment. By combining theexpertise of different disciplines, feedback toeach other is given, quality of care increasesand circumstances in which to receive optimaltreatment are guaranteed. However, a minimumcaseload is necessary.

Radiotherapy

The third important factor for local controlis radiotherapy. Radiotherapy after lumpectomydecreased the local recurrence rate from 8.8% to2.7% in the NSABP B06 trial (total mastectomyversus lumpectomy versus lumpectomy followedby radiotherapy) 20. These results and similarresults of other studies were confirmed by theresults of the meta-analysis from the EBCTCG of2000. Using radiotherapy after lumpectomy de-creased local recurrence; however, no differencein mortality was seen 40. The most recent EBCTCGmeta-analysis used almost 80 trials including42,000 patients with a follow-up of 15 years 41.This meta-analysis again showed a decrease inlocal recurrence rate after using radiotherapy.After five years, local recurrence rate was 26%without radiotherapy and 7% with the use of

S8 J.G.H. van Nes, C.J.H. van de Velde

Table 4Take home messages

A mastectomy with/without reconstruction is an acceptable alternative compared with breast-conserving therapyand should be discussed when treating young women for early breast cancer

Local control and survival for young women depends on the local treatment

Never accept positive margins in young patients!

Breast cancer requires a multidisciplinary approach

A predicted model for local treatment is needed 45

radiotherapy (reduction of 19%). This time therewas also a decrease in mortality: the 15-yearbreast cancer mortality risk was 35.9% withoutradiotherapy and decreased to 30.5% with the useof radiotherapy (reduction of 5.4%, 2p = 0.0002).This EBCTCG meta-analysis demonstrated thatlarge differences in local control produce littledifference in mortality during the first few years,but distinct differences in the 15-year mortality.One breast cancer death is avoided for every fourlocal recurrences avoided 42.

Chemotherapy

The last factor discussed for local control ischemotherapy. Over the years, the developmentand use of chemotherapy drugs have resultedin better treatment for patients with breastcancer. The EORTC trial 10854 is the so-calledPOP trial 42. Patients (n = 2795) were randomisedbetween surgery followed by one course ofpolychemotherapy (fluorouracil, doxorubicin andcyclophosphamide) within 36 h of the operationversus surgery alone. In a multivariate analysis,young age (<43) is the most important riskfactor for local recurrence (HR 2.75). However,this risk is greatly reduced by one course ofpolychemotherapy (fluorouracil, doxorubicin andcyclophosphamide). Since the POP trial – patientswere included from 1986 to 1991 – a large numberof new approaches have been studied to improvethe activity and reduce the uninvited side effectsof chemotherapy. Clinical trials on a worldwidebasis have been introduced, which compare newtreatments with the standard treatments. In thelast decade, indications for the use of systemictreatment have increased with an effect on (local)treatment outcome. We have to emphasise thelong-term follow-up of young patients treated withchemotherapy.

Psychological outcome

The psychological part of surgical treatment isvery important when operating on young women

with breast cancer. Intuitively, both patient anddoctor naturally prefer BCT over mastectomy.However, not all studies indicate that breast-conserving correlates with improved psychologicaloutcome. An American trial evaluated psycholog-ical aspects after breast cancer surgery. Patients(n = 183) were interviewed using the Mental HealthInventory test 43. With this test, five dimensionsof psychological distress were evaluated; anxiety,depression, loss of emotional control, positiveeffect and interpersonal ties. It appears thatpatients who received BCT felt better in the firstmonths after surgery. However, as time passed,they started to feel worse. They were afraidand concerned about local recurrence. In patientswho received a mastectomy, it was the otherway around. When reviewing medical studiescomparing the effect of mastectomy and BCTon quality of life, no major differences werefound in psychological adjustment, change oflife patterns, fears and/or concerns 44, although,patients treated with BCT had an improved bodyimage and sexual functioning. This means thatbreast reconstruction can play an important rolein patients treated with mastectomy.

Conclusion

The local recurrence rate of patients with breastcancer depends on local control. Independent riskfactors for local control are young age, surgicaltreatment options, positive surgical margins afteroperations due to DCIS or invasive breast cancerand BCT without radiotherapy (Table 4). Thesurvival rate is generally equal after mastectomyor BCT. However, after a longer follow-up, BCTis associated with a higher local recurrencerate. Young women have a longer lifespan, andare thus at a higher risk of local recurrenceleading to higher mortality in the end. Therefore,mastectomy with or without reconstruction shouldbe considered and discussed with every youngwoman with breast cancer. Mastectomies offerbetter local control and may be associated witha better psychological outcome in the long run.

Preferred treatment for young women with breast cancer – mastectomy vs. breast conservation S9

Halsted thought that breast cancer arose fromone location and would spread outward. Thisstressed the need for radical surgery. At the endof the last century, it was considered that breastcancer was a systemic disease, and BCT becamepossible. Nowadays, new data suggests that localrecurrence, distant recurrence and overall survivalare related. Decreasing local recurrences will haveimpact on overall survival. In addition, patientswant to play a role in their treatment decision.

Therefore, breast cancer requires a multi-disciplinary approach in order to provide theoptimal treatment for each patient. We haveto involve the young patient in the decisionof her treatment: mastectomy versus BCT. Thepossibility of reconstruction should also bediscussed. The normograms that are available(e.g. www.adjuvantonline.com) are based onsystemic therapy and there are no decision modelsspecifically for local treatment. However, mostof these decision models regard breast canceras a systemic disease. There is a need for moreand better (interactive) predictive models andinformation to assist both the physician andthe patient in choosing the optimal locoregionaltreatment for breast cancer.

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