Aebi, S.

Castiglione, M.

RERO DOC Digital Library

Annals of Oncology 17: 1475–1477, 2006doi:10.1093/annonc/mdl330editorialThe enigma of young ageBreast cancer in very young patients has traditionally beenconsidered as particularly aggressive and associated with a poorprognosis. The negative prognostic impact of young age hasbeen substantiated in numerous studies of clinical databases[1–4] including a recent population-based analysis of patientswith stage I breast cancer: After adjusting for tumor size,histological grade, estrogen receptor (ER) expression, and yearof diagnosis, the age at diagnosis was still a significant predictorwith each year younger than 45 years adding a relative 5% tothe risk of death from breast cancer [5]. The distinction betweenyoung and ‘very young’ premenopausal patients is fuzzy butmost investigators who chose to dichotomize their analysis usedan age limit of 35–40 years.It appears obvious that age by itself cannot explain the lessfavorable outlook of young patients with breast cancer butrather that age is a surrogate for biological features thatdetermine the more aggressive behavior of breast cancers inyoung women. Indeed, it is a common feature of most studiesinvestigating known prognostic factors in young women to findhigher proportions of poorly differentiated, rapidlyproliferating, ER- and progesterone receptor (PgR)-negativetumors that tend to be larger and to involve regional lymphnodes [3, 6, 7]; similarly, bone marrow micrometastases,another negative prognostic factor, are observed morefrequent in young patients [8]. In some of these analyses,multivariate modeling eliminated age as an independentprognostic factor [6, 9] but in many others the knownbiological factors did not completely explain the higherlikelihood of local [10] and distant recurrence conferred byyoung age [3, 4, 11].The interpretation of such retrospective data is confoundedby adjuvant therapies that modify the natural course of breastcancer and by temporal changes in the use of such therapies. Forinstance, the gradual reduction of breast cancer mortality from1988 to 1997 observed in a recent analysis of SEER data forpatients younger that 45 years with stage I breast cancer [5]could result from increased use of adjuvant systemic therapies inthe same time period. Indeed, the historically poor prognosismay be related to inadequate therapy as illustrated by data fromDenmark on the basis of a population of patients who werediagnosed with breast cancer from 1978 to 1996. Youngpatients who did not receive adjuvant systemic therapy due toapparent low-risk disease had a much higher probability ofrecurrence than older patients with otherwise similarcharacteristics. This negative impact of young age was notobserved in patients with higher risk breast cancer who didreceive adjuvant systemic therapy. While the use ofchemotherapy without hormonal therapy would be consideredsubstandard today, the omission of systemic therapy for veryyoung, seemingly low-risk patients might have contributed tothe poor prognosis [12].Adjuvant chemotherapy may act on at least two generalpathways: direct cytotoxic effects in cancer cells and endocrineeffects. While cytotoxicity is likely the main mechanism ofaction in breast cancers that do not express ER and PgR, thesuppression of ovarian function by chemotherapy may be theprincipal mode of action in ER-positive disease: continuingmenses is a strong predictor of an unfavorable outcome bothafter CMF-based [13–16] and after anthracycline-containingchemotherapy [17]. Obviously, the probability of developingamenorrhea depends on the age of the patient and on theregimen used [18]; it is therefore not possible to separatelyassess the effects of age and of amenorrhea. However, thesuppression of ovarian function for at least 2 years has beenfound to be at least as effective as CMF- and epirubicin-basedchemotherapy without endocrine therapy in at least eightrandomized controlled trials [19]; none of these trials reporteddifferential effects of endocrine or chemotherapy by age,although some confirmed an inferior prognosis for very youngpatients [15].Tamoxifen reduces the risk of relapse and death fromER-positive breast cancer; its efficacy does not depend onage and is not diminished by prior chemotherapy [20–22].Given these complexities, what does the paper reported byauthors of the European Institute of Oncology add? Colleoniand et al. [23] have analyzed their prospectively collecteddatabase of 841 premenopausal patients treated at theirinstitution for node-negative breast cancer, and they comparedthe prognostic factors, treatments, and outcomes between veryyoung (below 35 years of age) and older premenopausalpatients. As compared to previously reported series, their dataare derived from a relatively recent period such that thetreatments used are still relevant for today’s practice.Unfavorable prognostic factors were more common in tumorsof very young patients as expected from other patient series.Despite a relatively standardized therapeutic approach includinghormonal therapy for the very young patients with ER-positivetumors, the very young patients were still found to havea significantly higher risk of relapse and death than olderpatients. This was especially true for patients with ER-positivetumors who did not receive appropriate adjuvant therapy; thisobservation, while biologically plausible, is based on a subgroupof 18 patients, such that firm conclusions cannot be drawn.Multivariate analyses of survival did not eliminate age asa prognostic factor despite adjusting for tumor size, vascularinvasion, proliferation fraction, ER and PgR, andoverexpression of HER-2 protein.editorialª 2006 European Society for Medical OncologyThus, even in a relatively recent population of patients withnode-negative early breast cancer that was diagnosed andtreated in a reasonably short time period at a singleinstitution, the typical prognostic factors did not fully explainthe negative impact of young age. Recently, the developmentof high-throughput molecular methods has enabledresearchers to establish prognostic RNA expression profiles.Several groups have demonstrated that such profiles were ableto predict the outcome of breast cancer more accurately thantraditional prognostic factors [24–26]. Of particular interestin this context is the analysis of van de Vijver et al. [25]: Theproportion of patients with a poor-prognosis gene signaturewas inversely correlated with age; such signatures were mostfrequently observed among the youngest women. Whileyoung age was a negative prognostic factor on univariateanalysis, it was not an independent factor in a multivariateanalysis including the gene signature. While similar resultshave been reported by using the more traditional Nottinghamprognostic score [27], the molecular approach offers thepotential to investigate the specific mechanisms ofcarcinogenesis leading to breast cancer at a very young ageand to develop therapies that target the involved molecularaberrations. In this context, a recent publication from theAmsterdam group deserves to be mentioned as an example:Dai et al. [28] demonstrated in an analysis of 311 breastcancer samples that while there is on average a positivecorrelation of ER expression with age, there isa subpopulation of young women whose cancers expressa particularly high level of ER for their age. The cancers of thissubgroup have a poor prognosis and are characterized bya strong expression of cell cycle-associated genes [28]. Whilethese findings cannot yet be translated directly intotherapeutic recommendations, they offer a first molecular clueas to why very young patients with ER-positive breast cancertend to have a worse prognosis than patients with ER-negativedisease as observed by Colleoni et al. [23] in patients who didreceive appropriate therapy as well as by other groups inyoung patients who were treated with chemotherapy butwithout adjuvant hormonal treatments [29].The question why breast cancers in very young patients, inparticular below the age of 35–40, tend to carry a poorerprognosis than in older patients remains unanswered; asa logical consequence, there are no therapies that are specificallytailored to the characteristics of such tumors with the exceptionof conventional hormonal agents for patients with ER- or PgR-positive breast cancer. Studies with conventional prognosticfactors have exhausted their potential, and any progress willbe based on the investigation of molecular events leading toand promoting the development of breast cancer. In themeantime, the best therapy for very young patients is in theframework of a clinical study such as SOFT, TEXT, orPERCHE (http://www.ibcsg.org).S. Aebi1*, M. Castiglione21Department of Medical Oncology, University HospitalBerne, Inselspital PT2C, 3010 Berne, Switzerland;2International Breast Cancer Study Group CoordinatingCenter, Bern, Switzerland(*E-mail: stefan.aebi@insel.ch)references1. Adami HO, Malker B, Holmberg L et al. The relation between survival and age atdiagnosis in breast cancer. N Engl J Med 1986; 315: 559–563.2. de la Rochefordiere A, Asselain B, Campana F et al. Age as prognostic factor inpremenopausal breast carcinoma. Lancet 1993; 341: 1039–1043.3. Nixon AJ, Neuberg D, Hayes DF et al. Relationship of patient age to pathologicfeatures of the tumor and prognosis for patients with stage I or II breast cancer.J Clin Oncol 1994; 12: 888–894.4. Dubsky PC, Gnant MF, Taucher S et al. Young age as an independent adverseprognostic factor in premenopausal patients with breast cancer. Clin BreastCancer 2002; 3: 65–72.5. Aebi S, De Ridder M, Vlastos G et al. Young age is a poor prognostic factor inwomen with stage I breast cancer. Eur J Cancer 2006; (Suppl 4): 121.6. Albain KS, Allred DC, Clark GM. Breast cancer outcome and predictorsof outcome: are there age differentials? J Natl Cancer Inst Monogr 1994;35–42.7. Colleoni M, Rotmensz N, Robertson C et al. Very young women (<35 years)with operable breast cancer: features of disease at presentation. Ann Oncol2002; 13: 273–279.8. Braun S, Vogl FD, Naume B et al. A pooled analysis of bone marrowmicrometastasis in breast cancer. N Engl J Med 2005; 353: 793–802.9. Kollias J, Elston CW, Ellis IO et al. Early-onset breast cancer—histopathologicaland prognostic considerations. Br J Cancer 1997; 75: 1318–1323.10. Vrieling C, Collette L, Fourquet A et al. Can patient-, treatment- andpathology-related characteristics explain the high local recurrence ratefollowing breast-conserving therapy in young patients? Eur J Cancer 2003; 39:932–944.11. Love RR, Duc NB, Dinh NV et al. Young age as an adverse prognostic factorin premenopausal women with operable breast cancer. Clin Breast Cancer2002; 2: 294–298.12. Kroman N, Jensen M-B, Wohlfahrt J et al. Factors influencing the effect ofage on prognosis in breast cancer: population based study. BMJ 2000; 320:474–479.13. Pagani O, O’Neill A, Castiglione M et al. Prognostic impact of amenorrhoea afteradjuvant chemotherapy in premenopausal breast cancer patients with axillarynode involvement: results of the International Breast Cancer Study Group (IBCSG)trial VI. Eur J Cancer 1998; 34: 632–640.14. Boccardo F, Rubagotti A, Amoroso D et al. Cyclophosphamide, methotrexate, andfluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatmentof estrogen receptor-positive pre-/perimenopausal breast cancer patients:results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial.J Clin Oncol 2000; 18: 2718–2727.15. Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial oftamoxifen and goserelin versus cyclophosphamide, methotrexate, andfluorouracil: evidence for the superiority of treatment with endocrine blockade inpremenopausal patients with hormone-responsive breast cancer—AustrianBreast and Colorectal Cancer Study Group trial 5. J Clin Oncol 2002; 20:4621–4627.16. Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide,methotrexate, and fluorouracil as adjuvant therapy in premenopausal patientswith node-positive breast cancer: the Zoladex Early Breast Cancer ResearchAssociation study. J Clin Oncol 2002; 20: 4628–4635.17. Parulekar WR, Day AG, Ottaway JA et al. Incidence and prognostic impact ofamenorrhea during adjuvant therapy in high-risk premenopausal breast cancer:analysis of a National Cancer Institute of Canada Clinical Trials GroupStudy—NCIC CTG MA.5. J Clin Oncol 2005; 23: 6002–6008.18. Petrek JA, Naughton MJ, Case LD et al. Incidence, time course, anddeterminants of menstrual bleeding after breast cancer treatment: a prospectivestudy. J Clin Oncol 2006; 24: 1045–1051.19. Aebi S. Special issues related to the adjuvant therapy in very young women.Breast 2005; 14: 594–599.20. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy andhormonal therapy for early breast cancer on recurrence and 15-year survival: anoverview of the randomised trials. Lancet 2005; 365: 1687–1717.editorial Annals of Oncology1476 | Aebi & Castiglione Volume 17 | No. 10 | October 200621. Davidson NE, O’Neill AM, Vukov AM et al. Chemoendocrine therapy forpremenopausal women with axillary lymph node-positive, steroid hormonereceptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol2005; 23: 5973–5982.22. International Breast Cancer Study Group. Tamoxifen after adjuvantchemotherapy for premenopausal women with lymph node-positive breastcancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol2006; 24: 1332–1341.23. Colleoni M, Rotmensz N, Peruzzotti G et al. Role of endocrine responsiveness andadjuvant therapy in very young women (below 35 years) with operable breastcancer and node negative disease. Ann Oncol 2006; 17: 1497–1503.24. van’t Veer LJ, Dai H, van de Vijver MJ et al. Gene expression profiling predictsclinical outcome of breast cancer. Nature 2002; 415: 530–536.25. van de Vijver MJ, He YD, van’t Veer LJ et al. A gene-expression signature asa predictor of survival in breast cancer. N Engl J Med 2002; 347: 1999–2009.26. Wang Y, Klijn JGM, Zhang Y et al. Gene-expression profiles to predict distantmetastasis of lymph-node-negative primary breast cancer. Lancet 2005;365: 671.27. Blamey R, Mitchell M, Macmillan R et al. Young age is not an independentprognostic factor. Eur J Cancer 2006; (Suppl 4).28. Dai H, van’t Veer L, Lamb J et al. A cell proliferation signature is a marker ofextremely poor outcome in a subpopulation of breast cancer patients. Cancer Res2005; 65: 4059–4066.29. Goldhirsch A, Gelber RD, Yothers G et al. Adjuvant therapy for very young womenwith breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr2001; 30: 44–51.Annals of Oncology editorialVolume 17 | No. 10 | October 2006 doi:10.1093/annonc/mdl330 | 1477

The enigma of young age

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library