1. بسم الله الرحمن الرحيم

2. PRIMARY BREAST CANCER ESMO CLINICAL RECOMMENDATIONS FOR DIAGNOSIS,TREATMENT & FOLLOW UP

3. incidence In 2006 the estimated age-adjusted annual incidence of breastcancer in the European Union (25 countries) was 110.3/100 000and the mortality 25.0/100 000. The mortalityrate has decreased especially in younger age groups becauseof earlier detection and improved treatment. However, breastcancer is still the leading cause of cancer-related deaths inEuropean women.

4. Diagnosis

5. The diagnosis is based on the triad of clinical, radiologicaland pathological examinations. Clinical examination includesbi-manual palpation of the breasts and local regional lymphnodes.

6. Radiological examinations include bilateral mammographyof the breasts and ultrasound of the breasts and local regionallymph nodes. MRI of the breasts is not a routine procedure,but may be considered in cases involving diagnostic challengesarising, for example, because of dense breast tissue or positiveaxillary lymph node status with occult primary tumor in thebreast

7. Pathological diagnosis should be based on core needlebiopsy obtained by manual, or preferably by ultrasound or stereotacticguidance. A core needle biopsy, or if that is not possible,at least a fine needle aspiration indicating carcinoma shouldbe obtained before any surgical operations.

8. Final pathological diagnosis should be made according to the World Health Organization classification and the tumor–node–metastasis (TNM) (International Union Against Cancer and American Joint Committee on Cancer, sixth edition 2002) staging system analyzing all tissue removed.

9. Staging and risk assessment

10. In case of preoperative systemic treatment, a full clinical staging should be carried out at the outset. • In case of primary surgery, pathologic TNM staging based on hematoxylin–eosin staining, description of histologic type, standardized grading and evaluation of resection margins should be reported.

11. Determination of estrogen receptor (ER) and progesterone receptor (PgR) status is mandatory, preferably by immunohistochemistry [III, B].Reports of immunohistochemical results for ER and PgR should include the percentage ofER-and PgR-positive cells.

12. Hormone receptors are no longer included among the prognostic factors but are the mostrelevant predictive factor for the choice of treatment.

13. Immunohistochemical determination of HER2 receptor expression should be carried out at the same time for treatment planning.

14. When semiquantitative results of immunohistochemistry are ambiguous (++), in situ hybridization(FISH or CISH) to determine HER2 gene amplification shouldbe carried out. It is possible to directly carry out a gene amplification study (FISH or CISH) and not carry out the HER2 immunohistochemistry at all.

15. staging and risk assessment

16. Routine staging examinations include physical examination, full blood counts, routine chemistry including liver enzymes, alkaline phosphatase, calcium and assessment of menopausal status. This staging is needed for all patients and it can be acceptable for patients with small clinical tumors (T1) and without palpable nodes.

17. For all other cases and in particular for candidates to preoperative treatment, the conduct of additional investigations should be considered prior rather that after surgery.

18. In patients with higher risk (pathological N2 with four or more positive axillary nodes or T4 tumors or with laboratory signs or clinical signs or symptoms suspicious for the presence of metastases) : • Chest X-ray, • Abdominal ultrasound • Isotopic bone scan are appropriate [III, B].

19. Postoperatively the pathologist's report should include: 1-numberof tumors in the tissue removed, 2-the maximum diameter of thelargest tumor (T), 3- histologic type and 4- grade of the tumor, 5- evaluationof the resection margins including the minimum margin in millimetresand its anatomical direction;

20. 6-total number of removed lymphnodes, 7- number of positive lymph nodes, 8- extent of metastasesin the lymph nodes (ITC, micrometastatic, metastatic), i.e.N-status

21. The report should also include: 9-immunohistochemical evaluation of ER and PgR using a standardizedassessment methodology, 10- immunohistochemicalevaluation of HER2 receptor expression. HER2 gene amplificationstatus may be determined directly from all tumors using in situhybridization (FISH or CISH) or only from tumors with an ambiguous(2+) immunohistochemistry. Vascular and lymphovascular invasionshould also be reported.

22. Treatment decisions are based: • Primarily on endocrine responsiveness of the tumor. • Secondarily on risk of recurrence.

23. Definition of risk categories for patients with operated breast cancer

24. Risk stratification: has been revised and currently includes three risk groups: • Low • Intermediate • High risk • Vascular invasion has been described as an important prognostic factor, particularly in node-negative disease.

28. Treatment Plan

29. Treatment planning should be done by a multidisciplinaryteam including : • A surgical, • A medical • A radiation oncologist. • A pathologist in order to integrate local and systemic therapies as well as their sequence [III, B].

30. The possibility of hereditary cancer should be explored and counseling of relatives should be considered [IV, D] .

31. local therapy :non-invasive carcinomaIntraductal carcinoma (ductal carcinoma in situ, DCIS) may betreated with breast-conserving surgery (BCS) providing healthytissue margins can be reached. There is no general consensuson what is regarded as a safe (negative) margin. However, margins>10 mm are adequate and margins <1 mm are inadequate.

32. Adjuvant breast irradiation after BCS decreases the risk oflocal recurrence but has no effect on survival However, in some patients with low-risk DCIS (tumorsize <10 mm, low/intermediate nuclear grade, adequate surgicalmargins), the risk of local recurrence following excision onlyis so low that omitting radiation may be an option.

33. Especiallyin ER-positive DCIS tamoxifen may be considered following BCS(with or without adjuvant radiation)

34. Total mastectomywith clear margins in DCIS is curative, and radiation therapyis not recommended. In this group of patients tamoxifen mayalso be considered as a risk reduction therapy to decrease therisk of contralateral breast cancer

35. When ductal carcinoma in situ (DCIS) is treated by breast-conserving surgery, all subgroups of patients benefit from adjuvant radiation (I, A). Adjuvant tamoxifen should be considered in women with ER-positive DCIS (II, B), while its use in patients with ER-negative disease may be detrimental.

36. Lobular carcinoma in situ(LCIS) is a risk factor for future development of invasive cancer. It should be completely resected.

37. Local Therapy: 2- Invasive Carcinoma

38. Operable breast cancer :is initially treated by surgery, using breast-conserving surgery or mastectomy, both in combination with axillary dissection or a sentinel node biopsy.

39. Contraindications to BCSinclude : *Multicentric tumors, *Large tumors (>3–4 cm)in small breasts especially when no neo-adjuvant therapy isplanned, * Positive margins after resection, *Inflammatory breastcancer and *Patient's own wish.

40. Sentinel node biopsy

41. Clinical Recommendations • Sentinel node biopsy should not be carried out: • In case of palpable axillary nodes, • T3 or T4 tumors, • Multicentric tumors • Prior axillary surgery • Large biopsies • After breast reconstruction or implantation of a prosthesis • During pregnancy or lactation • After neo-adjuvant systemic treatment outside of clinical trials.

42. -Breast radiotherapy is strongly recommended after breast-conserving surgery [I, A]. • -Postmastectomy radiotherapy has been recommended for patients: • With four or more positive axillary nodes . • Is suggested for all T3 tumors .

43. -Post-mastectomy radiotherapy may also be consideredin cases of at least T1 tumor with 1–3 positive axillarylymph nodes, particularly if young, -and in cases of T2 or greatermedially located tumors which show signs of biological aggressiveness(receptor-negative, grade 3, HER2-positive, high proliferationactivity, e.g. Ki-67).

44. Postoperative Radiotherapy reducesthe risk of local recurrence by two-thirds and has a beneficialeffect on survivaL

45. In patients >70 years of age who havereceptor-positive invasive breast cancer with maximum stagepT1N0 and clear postoperative margins it may be possible touse adjuvant tamoxifen instead of radiation therapy [II, B].

46. PRIMARY SYSTEMIC THERAPY: Before primary systemic therapy, a biopsy for histology and analysis of predictive factors should be carried out. In addition, for these higher risk patients, a full clinical staging to rule out metastatic disease is necessary.

47. Primary systemic therapy: is indicated for locally advanced breast cancer (stage IIIA, IIIB, IIIC) [III, B].

48. It can employ chemotherapy or endocrine therapy on the basis of predictive factors similar to adjuvant treatment.

49. Trastuzumabshould be considered in the treatment protocol in HER2-positivetumors. It should be followed by both surgery and radiotherapyand postoperative systemic adjuvant treatment

50. If possible it should be followed by both surgery and radiotherapy and postoperative systemic treatment .