Carcinoma della mammella Her2 positivo Ruolo della radioterapia

1. Università degli Studi “G. D’Annunzio” Facoltà di Medicina e Chirurgia Scuola di Specializzazione in Radioterapia Prof. Giampiero Ausili Cefaro CHIETI Carcinoma dellamammella Her2 positivo Ruolodellaradioterapia Dott.ssa M. Trignani

2. Opzione standard Chirurgia conservativa + Radioterapia EARLY BREAST CANCER BCS + RT vs Mastectomia Milano I, NSABP, EORTC, IGR, NCI, DBCG

3. Pooled-Analysis 9422 paz Rischio relativo (RR) di Rec. Locale= 3 BCS + RT vs sola BCS Rischio relativo (RR) di morte= 1,086 BCS + RT vs sola BCS Beneficio RT Beneficio RT No beneficio RT No beneficio RT Vincent V-H,J Natl Cancer Inst 2004

4. Principali parametri che influenzano la recidiva locale • Dimensioni del T • Margini • Grading • EIC • Età

5. 1901 pz Komoike Y, Cancer 2006

7. Over the past ten years, the genomic analysis has revolutionized research in oncology. Mammary tumors 5 "molecular subtypes" characterized by different aspects of gene expression Sorlie T Proc Natl Acad Sci USA 98(19):10869-74 Make a clinic decision Molecular subtypes Tayloring locoregional and sistemic treatment

8. Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. • About 60% to 70% of breast carcinomas express ER protein, and these tumors are associated with better prognosis. Thike AA, Chng MJ, Chong SF, et al. Pathology. 2001;33:21-25. • ER status is important in predicting the response to adjuvant tamoxifen (hormonal) therapy. PR is a surrogate marker of functional ER because PR is an estrogen-regulated gene. • More than half of ER+ tumors express PR. Hence, simultaneous analysis of ER and PR gives more information regarding likely hormonal response. • ER, PR and HER2 are indipendent prognostic and predictive biomarkers Esteva FJ Breast Cancer Res 2004;6:109-118 Payne SJ Hystopathology 2008; 52:82-90

9. TAILORING OF MEDICAL THERAPY Hormone therapy remains the mainstay for hormone receptor–positive breast cancer. The decision for hormone treatment has traditionally relied on assessment of ER and PR status of primary tumors, with the response generally related directly to ER and PR content. The efficacy of trastuzumab is highly dependent on the c-ERBB2 status of the tumor and in the metastatic breast cancers that overexpress c-ERBB2 has been proven.

10. TAILORING OF LOCOREGIONAL TREATMENT ? Studies specifically relating receptor status of primary tumors with local recurrences are also few. Few published reports regarding the comparison of c-ERBB2 status between the primary and metastatic or locally recurrent sites. Am J Clin Pathol 2010;133:416-429 Few studies have examined these biomarkers as predictors of locoregional recurrence (LRR)

11. Am J Clin Pathol 2010;133:416-429

12. To identify patients who had an increased risk of LRR and therefore might benefit from adjuvant systemic treatment or more aggressive local treatment uniform evaluation of ER, PR, and HER2 expression. Whole breast 50 Gy in 25 fractions using medial and lateral tangent fields, followed by a tumor bed boost of 10 Gy in 5 fractions. RT 60 Gy

13. Tumors ER or PR positive were categorized as HR positive. Tumors that were both ER and PR negative were categorized as HR negative resulting in four tumor subtypes: HR+HER2, HR+HER2+, HRHER2+, and HRHER2. The 8-year LRR rate was greater in patients with ER-negative disease, PR-negative disease, and HER2-positive (17.5% vs. 3.9%, p = .009).

14. HER2-positive breast cancer and ER/PR-negative disease independently predicted for LRR. Additionally, close/positive margins (with close defined as <2 mm) and lobular histologic features continued to predict for LRR.

16. HER2 STATUS Patients who have HER2-positive tumors 1 cm or smaller have a high risk of relapse and consequently a shorter recurrence-free survival time. SUBTYPES

17. Multivariate analyses confirmed the prognostic role of HER2 status on locoregional recurrence

18. Was investigated the potential association between biological subtype and increased risk of LRR compared with conventional prognostic factors. • Patients baseline characteristics stratified by biological subtype (4 subgroups HR±/HER2±). • On multivariate analysis HR-/HER2+ and LN (>1) were found indipendent prognostic factors with increased risk of LRR after BCT. • For the subgroups radical mastectomy on multivariate analysis triple negative and LN (>1) were found prognostic factors. RT to the breast(42.5–50 Gy in 16–25 fractions) was offered to all patients after segmental resection; regional LN irradiation being offered if 4 LN-positive. Post-mastectomy chest wall and regional LN irradiation (45–50 Gy in 20–25 fractions) if they had LN positive or T3.

22. Triple negative, Rec-/HER2+, Rec+/HER2+ are an increased risk of LRR after radical mastectomy. Ipsilateral chest wall and supraclavicular region of lymph nodes irradiation with a total dose of 50 Gy, 2 Gy per fraction, over a 5-week period. No difference of LRFS between HER2+ and HER2-

23. The mechanism explaining how HER2 positivity predicts for LRR is unknown. • HER2 positivity predicted for LRR in the BCT subgroup. • HER2-positive tumors might have been resistant to post-lumpectomy radiotherapy. • These data suggestthat ER/PR-negativeand HER2-positive patients might benefit from chemotherapy, anti-HER2 therapy, or more aggressive locoregional therapy, even in very early-stage disease.

25. CHIETI UNIVERSITY RADIOTHERAPY PERICOLO RICADUTA

26. OUR EXPERIENCE

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29. OUR EXPERIENCE: SUBTYPES

30. MILESTONES • HER2-positivity predicts for recurrence, with an increased risk of LRR. • These issues seem to be confirmed in patients HER2+ surgically treated or conservatively than with mastectomy. • Given the risk of relapse, HER2-positive patients might benefit from chemotherapy, anti-HER2 therapy, or more aggressive locoregional therapy, even in very early-stage disease. Which is the more aggressive loco regional treatment that should be considered?

31. YOUNG BOOST TRIAL : essai de phase 3, randomisé évaluant de l’augmentation de dose de radiothérapie au lit tumoral, chez des femmes jeunes ayant cancer du sein [fiche d’essai clinique sur Internet]. Boulogne-Billancourt : Institut national du cancer. Disponible à l’adresse: https://www.e-cancer.fr/les-essaiscliniques/registre-des-essais-cliniques (accès le 22/6/2011). WHICH IS THE MORE AGGRESSIVE LOCOREGIONAL TREATMENT THAT SHOULD BE CONSIDERED? • BOOST: increase the dose to the tumor bed; • WHOLE BREAST: increase the dose to the whole breast; • NODAL IRRADIATION: irradiation of the clavicularregion even if less than 4 lymph nodes involved. • RT associated to adjuvant trastuzumab. Trastuzumabadjuvanttoradiotherapyincreaseradiosensitivity and couldbeassociatedwithreductionof LRR. Trastuzmab determinate cardiotoxicity..

33. Conclusion • Future prospective studies, including clinical trials, are needed to fully determine the utility of these biomarkers in guiding treatment decisions in this patient population. • Several forthcoming clinical trials have begun to address medical and loco regional therapy basing on molecular characteristics. • These prospective clinical trials, and other future trials, might provide insight as to whether combining radiotherapy with HER2-directed therapies.

34. Grazie dell’attenzione De la taille unique……..au sur-mesure…..ce n’est pas toujour facile!