Comparison between Pathologic Characteristics of Her2 Negative and Positive Breast Cancer in a Single Cancer Center in Jordan DR Majdi A. Al Soudi, MD, FACS Breast SuRGeon, KHH Breast Unit Royal Medical Services

Background Human epidermal growth factor 2(Her2) is a protein found in breast cancer cells. It is thought to have an impact on cell growth. Her2 status is a prognostic factor and is important in planning for the treatment of patients with Her2 positive breast cancer.

Relationship between Her2 and other breast cancer tumor markers Vascular endothelial growth factor (VEGF) VEGF is responsible for tumor angiogenesis A 2004 study of 611 patients with primary breast cancer showed a significant correlation between overexpression of HER2 and 2 VEGF isoforms (P<0.001) The aggressive phenotype of HER2-overexpressing tumors may be due in part to VEGF Estrogen (ER) and progesterone receptors (PR) In a study by Seshadri et al (N=1056), HER2 overexpression was significantly associated with negative ER and PR status (P<0.00001 and P<0.0006, respectively) Hormones such as estrogen and progesterone may suppress HER2 expression, so that hormone-receptor–positive tumors are less likely to be HER2-positive . This interaction may explain why many HER2-positive tumors are unresponsive to hormone therapy

HER2 is a negative prognostic factor A landmark study by Slamon et al (N=189) showed a highly statistically significant correlation between HER2 gene amplification and shorter time to disease relapse (P<0.0001) as well as shorter overall survival (P=0.0011) In a study of patients with stage I-III disease (N=1056), 3-fold or greater gene amplification of HER2 was associated with significantly shorter disease-free survival (risk ratio=1.95, P=0.0027) HER2 gene amplification was also significantly associated with pathologic stage at diagnosis, axillary node involvement, and histologic subtype In an additional study of 580 node-negative patients, HER2 overexpression was associated with higher risk of disease recurrence (risk ratio=2.36, P=0.002)

Objective Her2 positive and Her2 Negative BC comparison regarding: Estrogen receptor(ER) and Progesteron receptor(PR) status, adverse prognostic factors such as lymphovascular involvement(LVI) and perineural involvement(PNI), lymphnode involvement, tumor histological grade tumor size, tumor histological type

Materials and Methods A retrospective study conducted in Al-Hussein Hospital in Amman from Jan 2009 till Jan 2013. This study revised the post operative histopathology reports of three hundred and sixty eight breast cancer cases. They were divided into Her2 negative and Her2 positive receptor status. The factors that were compared were ER and PR status, adverse prognostic factors (LVI and PNI), lymphnode involvement, tumor histological grade, tumor size and tumor histological type in women with Her2 negative and her2 positive breast cancer.

Distribution Regarding Her2 Status Total no of cases: 368

ER+ % ER- % Her2- 79.2% 20.8% Her2+ 56.25% 43.75% P Value: < 0.0001

PR+ % PR- % Her2- 74% 26% Her2+ 48.75% 51.25% P Value: < 0.0001

LVI+ % LVI- % PNI+ % PNI - % Her2- 50.35% 49.65% 25% 75% Her2+ 65% 35% 22.5% 77.5% P Value: 0.0226 P Value: 0.7689

Her2- Her2+ 0 LN % 26.74 % 31.25 % 1-3 LN % 25 % 4-9 LN % 22.22 % 26.25 % >9 LN % 18.75 % 17.5 % Her2- Her2+ 0 LN % 26.74% 31.25% LN+ % 73.26% 68.75% P Value: 0.4803

Her2- Her2+ G1 % 8.3% 3.75% G2 % 56.94% 40% G3 % 34.72% 56.25%

Her2- Her2+ T1 <=2cm % 19.44 % 15 % T2 2-5cm % 61.46 % 57.5 % T3 >5 cm % 19.1 % 27.5 %

Her2- Her2+ IDC % 92.5 % 82.99 % ILC % 5 % 14.24 % OTHER % 2.5 % 2.77 %

Summary Her2 -ve Her2 +ve 74% ER, PR positive 50% had ER, PR +ve 50.3% negative LVI 75% negative PNI 26.7% had no axillary LN involvement, 32.2% had 1-3 LN 56.9% had Grade 2 tumor 61.5% had tumor size between 2 and 5 cm (T2). 50% had ER, PR +ve 65% LVI positive 22% PNI positive 68.8% had axillary LN involvement. 53.8% had grade 3 followed by grade 2 40%. 57.5% had T2 tumors followed by T3 tumors in27.5%

Crosstalk between ER and Her2 Pathways The biological effects of estrogens on breast cancer cells are mediated through two nuclear receptors known as ER and ER β The binding of estrogen to ER induces phosphorylation of the receptor, triggering receptor dimerization and recruitment of coregulatory proteins, and facilitating the binding of the receptor to promoter regions of DNA and transcription Estrogen induces the expression of genes that encode proteins important for tumor growth, such as the insulin-like growth factor I receptor (IGF-IR), cyclin D1, collagenase, insulin growth factor II (IGF-II), and VEGF   Genes downregulated by estrogens include the EGFR and HER2

Conclusion Her2 negative tumors are associated with other favorable characteristics as ER, PR+ve, relative small sized tumors, moderate histological grade, and mostly limited number of involved LN Her2 positive tumors are more aggressive, more Lymphnode involvement, Er,Pr 50% -ve, positive LVI, less differentiated tumors, larger tumor size all in favour of a worse prognosis.

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