Dr Agher.N THE MOLECULAR CLASSIFICATION OF WOMEN’S BREAST CANCER, THERAPEUTIC INTEREST EXPERIENCE OF SIDI BEL ABBES, ALGERIA

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1 People's Democratic Republic of Algeria Ministry of Higher Education & Scientific Research Djillali Liabes of Sidi Bel-Abbes University Euro Midwifery & Women's Health November 13-14, 2017 London, UK THE MOLECULAR CLASSIFICATION OF WOMEN’S BREAST CANCER, THERAPEUTIC INTEREST EXPERIENCE OF SIDI BEL ABBES, ALGERIA N. AGHER N (1-2), A.TOU (1-2) (1) Djilali Liabes, Sidi Bel Abbes University, 22000, Algeria. (2)Pathology department, University hospital center Sidi Bel Abbes, 22000, Algeria

2 INTRODUCTION Breast Cancer = 1st Malignant Pathology and Women's Cancer Death in Algeria 1stCauseofof For many years - Breast cancer = single entity with therapeutic modalities. identical - The anatomo-clinical classification used tooptimize therapeutics is failing in a number of cases, leading overtreated or undertreated.

3 Currently: BreastCancer Very heterogeneous disease Biological entities Specific pathological characteristics Different clinical behavior Individualised of Treatment "Genetic map"

4 IntrinsicIntrinsicmolecular subtypeofofbreastbreastcancer Sorlie et Perou (2000) The phenotypic diversity of breast tumors Gene expression diversity

5 cDNA array

6 Intrinsic Classification 1.Luminal A 2.Luminal B 3.Her2 4.Basal 5.Normal breastlikelike

7 (24 %, n = 23) (25 %, n = 18) (18 %, n = 13) (10 %, n = 10) Luminal B Significant Prognostic Value of Intrinsic classification Basal Her2 Basal Her2 Luminal B Luminal A Luminal ALuminal A

8 Preliminary conclusions Classification still imperfect Non-robustness of the bioinformatic methods used for classify these tumors Lack of reproducibility of results obtained from a platform from molecular diagnostic to another Difficulty of realization in current practice, the need for frozen tumor material for the majority of these tests The impossibility of guaranteeing good quality RNAs of all operated breast tumors Alternative: Classic Anapath? Morpho and diagnostic criteria ++++ Reliable, standardized, reproducible IHC Clinical sense

9 Therefore, we have proposed, similarly to many series in the literature, to address this new molecular classification by a conventional immunohistochemical approach, validated as a replacement technique for microarray analysis.

10 Material and methods  237 cases of invasive breast carcinoma surgical specimens  2008 - 2014.  Identify the molecular class according to its IHC profile (RH, HER2, CK 5/6, P53).  Identify 4 subtype : luminal A, luminal B, HER2 and triple négative.  Classify triple negative tumors into basal-like or no basal-like (CK5/6, EGFR,P53)

11 Classification molecular of breastcancercancer  Luminal A: RE+ and/or RP+, HER2-.  Luminal B: RE+ and/or RP+, HER2+.  HER2: RE-, RP-, HER2+.  Triple Négatif: RE-, RP-, HER2-.  Nielsen et al : RE-, RP-, HER2-, CK5/6+, EGFR +, and/or P53+ : Basal-Like  RE-, RP-, HER2-, CK5/6 -, EGFR -, and/or p53+: No Basal-like.

12 Estrogen and progesteronereceptors:positive ≥10% (Europe) ≥1% (ASCO 2010) PRPR ERER

13 IHC négative (0 or +1) No membrane staining in 10% of tumor cells IHC equivocal (+2) need FISH Faint/barely perceptible or weak to moderate complete membrane staining detected in >10% of tumour cells IHC positive (+3) overexpression moderate to strong complete membrane staining in >10% of tumour cells

14 FISH : Fluorescence In SituHybridization - Average copy number of HER-2 / neu Negative: No amplification. <4:<4: -Average number of copies 4 to 6: Low amplification. ofofHER-2HER-2/neuneubetween -Average number of copies Positive: Amplification. ofofHER-2HER-2/ neu> 6:

15 PhenotypeofofBasal-likecarcinomas CK5/6EGFR

16 Results identified: and Discussion We have 16% 29% 35% 20% luminal tumors A, luminal tumors B, HER2 Triple negative tumors. The study of the expression of CK phenotype identified 5/6 and P53 for thetriple negative 84% of basal-like tumors 16% of non-basal-like tumors

17 Luminal A Phenotype  Contrary to the literature Luminal A tumors occupy the last row 16% of cases.  Infiltrative ductal type with frequent histological type of classic lobular carcinomas, mucinous and tubular.  Well to moderately differentiated tumors  In our study, age was between 40 and 49 years  pT2 stage.

18 Luminal B Phenotype  Contrary to the literature Luminal B tumors occupy the second row 29% of the cases,  The majority of which were infiltrative duct type  Well to moderately differentiated  In our study, age between 40 and 49 years  pT2 stage,

19 Prognosis of luminal tumors  Luminal group: the most favorable prognosis for all the molecular groups.  In the study by Cheang et al. British Columbian Cancer Agency (BCCA) series: Luminal group B was significantly associated with:  A young age at the time of diagnosis  Large tumor size and ganglionic involvement  A high histological grade  Survival rate without recurrence at 10 years = 53% (70% for luminal A)

20 Phenotype HER2  In our series, the molecular class HER 2 occupies the first position with 35% of cases. contrary literature.  Age is between 40 and 49 years with a percentage of 34%.  According to most series, the majority of these tumors are pT2 with a percentage of 54%.  Bad prognosis  Transtuzumab reduced the percentage of local relapses by 35% to 15% in the National Surgical Adjuvant Breast and Bowel Project study  (NSABP), 22 to 12% in the North Central Cancer Treatment Group Trial (NCCTG) and 3 to 1.6% in the Herceptin Adjuvant Trial

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22 Phenotype Basal-like  A triple negative breast tumor is defined by RH - and HER2-.  In practice, they are diagnosed by the search for the expression CK5-6 and / or EGFR and / or p53.  85% of basal-like tumors  15% of non-basal-like tumors.  The majority of patients were aged 40 and 49 years, unlike literature, it affected an older population.  As the results of Chukwuemeka et al., The majority of these tumors were pT2 stage

23 Triple negative breast tumors Group dominated by the basal-like type, but covers a heterogeneous set of tumors whose precise characterization will be necessary taking into account the different prognoses according to the subtypes and the necessary adaptation of the treatments

24 Multicenic classifiers (Oncotype DX, Mammaprint...) enjoy significant media coverage and are supported by large groups. These tests, all centralized, are expensive and are not yet available for all patients. The validation of these tests is still subject to criticism.

25 Finally

26  Understanding the biology of tumors  The signature of so-called "intrinsic" genomic expression that distinguishes several major categories of breast cancer has clearly shown its clinical relevance in terms of prognosis and even therapy.  Understanding sensitivity to different treatments  This requires the importance of developing adequate care for these patients (90 to 95% of therapeutic problems).  Installation of the necessary techniques for the therapeutic choice.  Its utility in current practice.

27 References Sgroi DC. Annu. Rev. Pathol. Mech. Dis. 2010 Hu et al. BMC Genomics 2006, 7, 96 Klintman et al, SABCS 2008, abstract 1076 Desmedt Clin Cancer Res 2008, 14, 5158-5165 Ali and Coombes Nat Rev Cancer 2002, 2, 101-115 Musgrove and Sutherland Nat Rev Cancer 2009,9,631-643 Lash et al. Lancet Oncol 2009, 10, 825-833 Hoskins et al. Nat Rev Cancer 2009, 9, 576-586 Viale J Clin Oncol 2008, 26, 5569-5575 Kouros-Mehr, Cell 2006, 127, 1041-1055 Asselin Labat Nat Cell Biol 2007, 9, 201-209 Mehra Cancer Res 2005, 65, 11259-11264 Badve Clin Cancer Res 2007, 13, 4415- 4421 Miller J Clin Oncol 2011, 29, 4452-4461

28 THANK YOU FOR ATTENTION