Bergh, J.

Jost, L. M.

Luporsi-Gely, E.

Pestalozzi, B. C.

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ESMO Minimum Clinical Recommendations for diagnosis,adjuvant treatment and follow-up of primary breast cancerIncidence. The crude incidence of breast cancer in the European Unionis 109.9/100 000 females per year, the mortality 38.4/100 000females per year, however with marked geographicalvariation.Diagnosis. The diagnosis is based on clinical palpation, bilateral mam-mography and ultrasound. Pathologic diagnosis with fineneedle aspiration or core needle biopsy should be obtainedprior to any surgical procedure. Final pathological diagnosisshould be made according to the World Health Organisationclassification and the TNM (2002) staging system analyzingall tissue removed.Staging and risk assessment. TNM-staging based on H&E staining, standardized grading,description of histologic type, and of resection marginsshould be reported. Determination of estrogen receptor (ER)and progesterone receptor (PR) status is mandatory, prefer-ably by immunohistochemistry [III, B]. Reports of immuno-histochemical results for ER and PR should include thepercentage of ER- and PR-positive cells. When available,immunohistochemical determination of HER2 receptorexpression should be performed at the same time. Whensemi-quantitative results of immunohistochemistry areambiguous ( + + ), in situ hybridization (FISH or CISH) todetermine HER2 gene amplification should be considered.. Routine staging examinations include physical examination,full blood counts, routine chemistry including liverenzymes, alkaline phosphatase, calcium; assessment ofmenopausal status.. In patients with higher risk (N2 with >_4 pos. axillary nodes,or T4 tumors, or with laboratory signs or clinical signs orsymptoms suspicious for the presence of metastases), chestX-ray, abdominal ultrasound and isotopic bone scan areappropriate [III, B].. Explore the possibility of hereditary cancer and evaluateadequate counselling of relatives [IV, D]. For node negativepatients the following risk stratification to guide adjuvanttreatment is recommended [III, B]. Even tumors smallerthan 1 cm can benefit from adjuvant treatment with che-motherapy and/or tamoxifen [II, B]. See Table 1.Treatment plan. Multidisciplinary treatment planning should be used to inte-grate local and systemic therapies as well as their sequence[III, B].Local therapyInvasive carcinoma. Generally, operable breast cancer is initially treated by sur-gery, using breast conserving surgery or mastectomy, bothin combination with axillary dissection. Contraindications tobreast-conserving surgery include multicentric tumors, largetumors (larger than 3–4 cm), tumor-involved margins afterresection. The technique of sentinel lymph node biopsy maybe used in centers with documented experience and accu-racy. Breast radiotherapy is strongly recommended afterbreast conserving surgery [I, A]. Post-mastectomy radiother-apy has been recommended for patients with four or morepositive axillary nodes [II, B] and is suggested for T3tumors with positive axillary nodes [III, B].Ductal carcinoma in situ (DCIS). When DCIS is treated by breast conserving surgery, all sub-groups of patients benefit from adjuvant radiation as well asfrom adjuvant tamoxifen [I, B]. Adjuvant tamoxifen forDCIS reduces the recurrence rate of in situ and of invasivebreast cancer.Primary systemic therapy. Primary systemic therapy is indicated for inoperable locallyadvanced breast cancer (stage IIIB: T4, N2-3, regional M1)[III, B]. If possible it should be followed by both surgeryand radiotherapy and postoperative systemic treatment.Primary systemic therapy is an alternative for largeoperable breast cancer, to allow breast conserving surgery[I, A].Adjuvant systemic therapy. Before deciding whether to use adjuvant systemic therapy,the prognosis without adjuvant therapy should be estimated.For each individual, the choice of adjuvant therapy musttake into account the potential benefits, possible side effects,and patient preference.Annals of Oncology 16 (Supplement 1): i7–i9, 2005doi:10.1093/annonc/mdi825q 2005 European Society for Medical OncologyTamoxifen. Patients with ER and/or PR positive tumors should receivetamoxifen 20mg/d for 5 years [I, A]. Patients with ER andPR negative tumors [I, A] and/or HER2-positive tumors [II,C] should not receive it. Tamoxifen should be started whenchemotherapy is completed [II, A]. Concurrent use oftamoxifen with radiation therapy is not recommended dueto potentially increased risk of lung toxicity [III, C].Aromatase inhibitors. The use of aromatase inhibitors in stead of or in sequencewith tamoxifen significantly reduces the risk of recurrencecompared with tamoxifen, but no survival benefit has beendemonstrated so far [I, A]. Furthermore, the absolute differ-ence in recurrence-free survival is <5%. The long-term car-diovascular and skeletal adverse effects associated witharomatase inhibitors are an issue of concern. Certain sub-groups (ER-positive/PR-negative, HER2-positive) seem tohave a more marked benefit by the use of an aromataseinhibitor [III, C].Ovarian ablation. Ablation of ovarian function is an alternative to CMF-basedregimens for premenopausal patients with endocrine respon-sive tumors [I, A]. Bilateral ovarectomy and irradiation ofthe ovaries lead to irreversible ablation of ovarian function.LHRH analogs generally lead to reversible ovarian suppres-sion. They should be given for at least 2 years [III, D].Chemotherapy. Adjuvant chemotherapy should use a combination regimen,as shown in Table 2 [I, A]. In node-positive and node-negative disease anthracycline-containing therapy has beenshown to be slightly superior in efficacy to intravenousCMF [I, A]. However, there seems to be a threshold dosefor adjuvant anthracyclines, below which efficacy becomesinferior [I, A]. 4 cycles of AC have been shown to be com-parable in efficacy to 6 cycles of CMF [I, A]. At the St Gal-len consensus conference 2003 4 cycles of AC or 6 cyclesof CMF were considered adequate treatment for ER and/orPR positive patients, while ER and PR negative tumors wereconsidered candidates for more prolonged chemotherapy.Adding 4 cycles of paclitaxel to 4 cycles of AC improvesoutcome in node-positive patients [I, A]. It is possible thatother more intensive anthracycline- and/or taxane containingregimens are equally effective. Encouraging results havebeen described with dose-dense therapy using hematopoieticgrowth factors in addition to AC and taxanes. This approachis not considered standard at the present time.Follow-up. History taking, eliciting of symptoms and physical examin-ation every 3–6 months for 3 years, every 6–12 months for3 years, then annually [A], with attention paid to long-termside effects, e.g. osteoporosis.. Ipsilateral (after breast conserving surgery) and contralateralmammography every 1–2 years [D].. Not routinely recommended for asymptomatic patients:blood counts, chemistry, chest X-ray, bone scan, liver ultra-sound, CT-scans of chest and abdomen, and any tumor mar-kers such as CA 15–3 or CEA [I, A].NoteLevels of Evidence [I–V] and Grades of Recommendation[A–D] as used by the American Society of Clinical OncologyTable 1.Tumor sizeER/PRa GradingAgeb CommentLow risk <2 cm positive 1 >_35 All factorsmust be presentHigher risk >_2 cm negative 2–3 <35 At least onefactor presentaUsing immunohistochemistry, ER/PR is usually considered positive,when >_10% of cells are positive (weakly or strongly) for either ER or PR[IV, B]. Some endocrine responsiveness seems to remain even when only1–10% of tumor cells are ER weakly positive [III, B]. ER and/or PRpositive patients are considered “endocrine responsive”.bNo exact age threshold has been defined.Table 2.Node Negative (N0) PatientLow risk, endocrineresponsiveTamoxifenORNilHigher risk, endocrine responsive:- Premenopausal Chemotherapy, ovarianablation ! tamoxifenORChemotherapy ! tamoxifenOROvarian ablation- Postmenopausal Tamoxifen*ORChemotherapy ! tamoxifenHigher risk, endocrine non-responsive:- Premenopausal Chemotherapy- Postmenopausal ChemotherapyNode Positive (N1) PatientEndocrine responsive:- Premenopausal Chemotherapy! tamoxifen± ovarian ablation- Postmenopausal Chemotherapy! tamoxifen*ORTamoxifen*Endocrine non-responsive:- Premenopausal Chemotherapy- Postmenopausal Chemotherapy*In postmenopausal patients, aromatase inhibitors (anastrozole, letrozole,exemestane) are an alternative.i8are given in square brackets. Statements without grading wereconsidered justified standard clinical practice by the expertauthors and the ESMO faculty.Literature1. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclopho-sphamide, methotrexate, and fluorouracil in node-positive breast can-cer: the results of 20 years of follow-up. N Engl J Med 1995; 332:901–906.2. Early Breast Cancer Trialists’ Collaborative Group. Polychemother-apy for early breast cancer: an overview of the randomised trials. Lan-cet 1998; 352: 930–942.3. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen forearly breast cancer: an overview of the randomised trials. Lancet1998; 351: 1451–1467.4. Goldhirsch A, Wood WC, Gelber RD et al. Meeting highlights: Inter-national Consensus Panel on the Primary Treatment of Early BreastCancer. Ninth International Conference on Primary Therapy of EarlyBreast Cancer. J Clin Oncol 2003; 17: 3357–3365.5. Fisher B, Bryant J, Wolmark N et al. Effect of preoperative che-motherapy on the outcome of women with operable breast cancer. JClin Oncol 1998; 16: 2672–2685.6. Early Breast Cancer Trialists’ Collaborative Group. Ovarian ablationin early breast cancer: overview of the randomised trials. Lancet1996; 348: 1189–1196.7. Early Breast Cancer Trialists’ Collaborative Group. Favourable andunfavourable effects on long-term survival of radiotherapy for earlybreast cancer: an overview of the randomised trials. Lancet 2000;355: 1757–1770.8. Recht A, Edge SB, Solin LJ et al. Postmastectomy radiotherapy: clini-cal practice guidelines of the American Society of Clinical Oncology.J Clin Oncol 2001; 19: 1539–1569.9. Fisher B, Dignam J, Wolmark N et al. Tamoxifen in treatment ofintraductal breast cancer: National Surgical Adjuvant Breast andBowel Project B-24 randomised controlled trial. Lancet 1999; 353:1993–2000.10. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes fromadding wequential paclitaxel but not from escalating doxorubicin dosein an adjuvant chemotherapy regimen for patients with node-positiveprimary breast cancer. J Clin Oncol 2003; 21: 976–983.11. Raimund Jakesz, Hubert Hausmaninger, Ernst Kubista et al. Random-ized adjuvant trial of tamoxifen and goserelin versus cyclophospha-mide, methotrexate, and fluorouracil: evidence for the superiority oftreatment with endocrine blockade in premenopausal patients withhormone-responsive breast cancer-Austrian Breast and ColorectalCancer Study Group Trial 5. J Clin Oncol. 2002; 20: 4621–4627.12. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’Group. Anastrozole alone or in combination with tamoxifen versustamoxifen alone for adjuvant treatment of postmenopausal womenwith early breast cancer: first results of the ATAC randomised trial.Lancet 2002; 359: 2131–2139.13. Greene FL, Balch CM, Fleming ID, et al. (eds): In AJCC (AmericanJoint Committee on Cancer) Cancer Staging Handbook: TNM Classi-fication of Malignant Tumors, sixth edition. New York: Springer-Ver-lag 2002.14. Coombes RC, Hall E, Gibson LJ et al. A randomized trial of exemes-tane after two to three years of tamoxifen therapy in postmenopausalwomen with primary breast cancer. N Engl J Med 2004; 350:1081–1092.15. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole inpostmenopausal women after five years of tamoxifen therapy forearly-stage breast cancer. N Engl J Med 2003; 349: 1793–1802.16. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concur-rent combination chemotherapy as postoperative adjuvant treatment ofnode-positive primary breast cancer: first report of Intergroup TrialC9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21: 1431–1439.17. Winer EP, Hudis C, Burstein HJ et al. ASCO technology assessmenton the use of aromatase inhibitors as adjuvant therapy in postmeno-pausal women with hormone receptor-positive breast cancer: Statusreport 2004. J Clin Oncol 2005; 23: 619–629.Coordinating authors for the ESMO Guidelines Task Force:B. C. Pestalozzi1, E. Luporsi-Gely2, L. M. Jost3 & J. Bergh41Invited author, Div. of Oncology, Universita¨tspital, CH-8091 Zu¨rich,Switzerland; 2Invited author, Centre Alexis Vautrin,Vandoeuvre-Les-Nancy Cedex, France; 3Invited author and member ofthe task force, Oncology, Kantonsspital, CH-4101 Bruderholz/BL,Switzerland; 4Assigned task force member, Clinical and MolecularOncology, Radiumhemmet, Karolinska Institute & University Hospital,171 76 Stockholm, SwedenApproved by the ESMO Guidelines Task Force: May 2003, last updateFebruary 2005.Correspondence to:ESMO Guidelines Task ForceESMO Head OfficeVia La Santa 7CH-6962 LuganoSwitzerlandi9

ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer

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