Breast cancer in young women : aspects on mortality and local recurrence

The general aim of the thesis was to gain increased insight into the long-term prognosis for young women with breast cancer. In a population-based cohort of 22,017 women with breast cancer, we studied prognosis by age. Women aged <35 (n=471), 35–39 (n=858) and 40–49 (n=4789) were compared with women aged 50–69. The cumulative 5-year relative survival ratio (RSR) and the relative excess risk (RER) of mortality were calculated. Women <35 years of age had a worse survival than middle-aged women, partly explained by a later stage at diagnosis. After correction for stage, tumor characteristics and treatment, young age remained an independent risk factor for death. The excess risk of death in young women was only present in stage I-II disease and was most pronounced in women with small tumors.

For in-depth studies on a large subpopulation from the original cohort (all 471 women aged <35 and a random sample of 700 women aged 35–69), we collected detailed data from the medical records, re-evaluated slides and produced TMAs from tumor tissue. Breast cancer-specific survival (BCSS), distant disease-free survival (DDFS) and locoregional recurrence-free survival (LRFS) by age were analysed. In a multivariate analysis, age <35 and age 35– 39 years conferred a risk in LRFS but not in DDFS and BCSS. The age-related differences in prognosis were most pronounced in early stage luminal Her2-negative tumors, where low age was an independent prognostic factor also for DDFS (HR 1.87 (1.03–3.44)).

To study the importance of proliferation markers for the long-term prognosis in young women, protein expression of Ki-67, cyclin A2, B1, D1 and E1 was analysed in 504 women aged <40 and in 383 women aged ≥40. The higher expression of proliferation markers in young women did not have a strong impact on the prognosis. Proliferation markers are less important in young women, and Ki-67 was prognostic only in young women with Luminal PR+ tumors. Age <40 years was an independent risk factor of DDFS exclusively in this subgroup (adjusted HR 2.35 (1.22-4.50)). The only cyclin adding prognostic value beyond subtype in young women was cyclin E1.

In a cohort of 469 women aged <40 and 360 women aged ≥40 we examined whether Her2 status assessed by silver enhanced in situ hybridization (SISH) for all cases, would reveal a proportion of women undiagnosed by routine Her2 testing and whether this would affect their prognosis. With SISH testing for all women, the Her2-positive rate increased from 20.0% to 24.4% (p<0.001), and similarly for women aged <40 and ≥40 years. Young women had Her2+ breast cancer twice as often as middle-aged women. Her2 amplification was present in 4.6% of cases scored 0 with IHC, while the corresponding proportions for scores 1+, 2+ and 3+ were 36.0%, 83.7% and 96.8%, respectively. All Her2 amplified cases, both true positive and false negative, had a significantly worse BCSS than the true negative cases.

List of scientific papers

I. Fredholm H, Eaker S, Frisell J, Holmberg H, Fredriksson I, Lindman H. Breast Cancer in Young Women: Poor Survival Despite Intensive Treatment. PLoS ONE. 2009; 4(11): e7695.
https://doi.org/10.1371/journal.pone.0007695

II. Fredholm H, Magnusson K, Lindström LS, Garmo H, Eaker Fält S, Lindman H, Bergh J, Holmberg L, Pontén F, Frisell J, Fredriksson I. Long-term Outcome in Young Women With Breast Cancer – a Population-based Study. Breast Cancer Res Treat. 2016; 160(1): 131-143.
https://doi.org/10.1007/s10549-016-3983-9

III. Fredholm H, Magnusson K, Lindström LS, Tobin NP, Lindman H, Bergh J, Holmberg L, Pontén F, Frisell J, Fredriksson I. Breast cancer in young women and prognosis – how important are proliferation markers? [Submitted]

IV. Fredholm H, Pontén F, Hikmet Noraddin F, Bergh J, Frisell J, Holmberg L, Fredriksson I. Her2 positive breast cancer in young women – the prognostic impact of Her2 expression by immunohistochemistry versus silver in situ hybridization (SISH) in a population-based cohort. [Manuscript]