High proliferation is associated with inferior outcome in male breast cancer patients

Abstract

Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the luminal subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to study proliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin-embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan-Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset of patients with high expression of cyclin A (hazard ratio (HR) 3.7; P ¼ 0.001) and B (HR 2.7; P ¼ 0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P ¼ 0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P ¼ 0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation. Modern Pathology (2013) 26, 87-94; doi:10.1038/modpathol.2012.145; published online 24 August 2012 Keywords: breast cancer; immunohistochemistry; male Male breast cancer represents 0.6% of all breast cancer and because of its rarity, specific treatment guidelines are lacking. Thus, male patients are treated according to the guidelines for female breast cancer. Breast cancer mortality among women has declined during the last decades because of improvements in diagnostic procedures and treatment, but the corresponding observation has not been made in male breast cancer. 1 Recent studies have indicated that males have a poorer survival than females, despite having received adjuvant treatment to the same extent. 2,3 In addition, studies on transcriptional and genomic levels have revealed important molecular differences between male and female breast cancer. In a recent study, Johansson et al 4 performed gene expression analyses in male breast cancer and concluded that male breast cancer tumors could not be classified into the intrinsic subtypes previously established in female breast cancer. In line with these data, comparative genomic hybridization demonstrated significant differences regarding DNA aberrations com...

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

“…Patients forming the Swedish cohort were identified through the Swedish National Cancer Registry. 19 Males diagnosed between 1990 and 2007 within the Lund and UppsalaOrebro regions that had available formalin-fixed paraffin-embedded tumor blocks, clinicopathological data and outcome data were included in the study. This work was carried out with approval from the Peter MacCallum Cancer Center Ethics Committee (Project No: 11/61) and the local ethics committee in Uppsala, Sweden (i2007/254), and the Lund University (2012/89).…”

Androgen receptor expression in male breast cancer predicts inferior outcome and poor response to tamoxifen treatment

“…However, Wang-Rodriguez and colleagues found better survival in ER-positive patients but did not find a benefit from treatment with tamoxifen (8) (http://www.pubmed central.nih.gov/articlerender.fcgi?artidZ314449&toolZ pmcentrez -B8). Recently, a Sweden study has found that patients undergoing adjuvant endocrine treatment had a poorer breast cancer survival compared with those cases without such treatment (9). The distinct hormone signal in both genders may be the cause of their different responses to anti-hormonal therapy.…”

A review of estrogen receptor/androgen receptor genomics in male breast cancer

“…In contrast to male disease, female rates of ERα-and/or PR-positivity are higher (Giordano et al 2004, Nilsson et al 2013. Notably, AR is highly expressed in male breast cancers (Zhou et al 2014) and has been found to be indicative of good outcome in male breast (Shaaban et al 2012) and poor outcome in hormone-refractory prostate cancer (Buhmeida et al 2006).…”

“…Male breast cancer is rare, accounting for around 1% of all breast cancers (Siegel et al 2016) and is frequently positive for ERα (91-95%) and/or PR (80-81%) (Giordano et al 2004, Nilsson et al 2013). The most well-known anti-estrogenic therapy is tamoxifen, which competitively blocks estradiol binding to the receptor, effectively inducing an alternative conformation of ERα ligand-binding domain (Shiau et al 1998), which prevents the formation of an active transcription complex (Zwart et al 2007) and inhibiting the onset of tumor cell proliferation programs (Severson et al 2016).…”