In this study, young (<40 years) and old (≥80 years) age was positively associated with a high BCSM. For women aged under 40 years, this was predominantly apparent for those with ALNI-negative breast cancer. An age of 80 years or more was a prognostic factor for high BCSM, independent of stage and diagnostic period.
Strengths and limitations
This study was conducted among women diagnosed between 1961 and 1991 and due to this some information of interest unfortunately could not be collected at the time of diagnosis. However, to our knowledge this is one of the largest population-based patient datasets with all women treated at the same institution. It consisted of 4,453 women, with a 10-year follow-up period for the entire cohort. No referrals were made to or from the hospital for patients with breast cancer. All women diagnosed with invasive breast cancer in Malmö between 1961 and 1991 were included, minimizing a potential selection bias. Age at diagnosis and breast cancer diagnosis was obtained for all patients from the Swedish Population Registry and the Swedish Cancer Registry. Both these registries are highly valid [19,20]. Histopathological examination was performed on all samples at a single pathology department; hence the reliability of tumor characteristics ought to have been high . Cause of death was obtained from the Swedish Cause of Death Registry. The validity of the Swedish Cause of Death Registry has been evaluated for cause of death amongst breast cancer patients diagnosed in Malmö in two studies and found to be highly accurate [16,21].
The most important data that we were not able to adjust for due to information not being collected were histological grade, hormone receptor status, and adjuvant treatment. Data on the type of operation and whether an axillary dissection was performed is displayed in Table 1. The results were stratified for diagnostic period, which may have decreased the risk of confounding caused by treatment. In all periods adjuvant therapy was in general given routinely according to factors such as age, and ALNI; factors that were included in the analysis. This may have adjusted for treatment to some extent. However, it is still likely that older women less frequently would have been given adjuvant treatment according to the guidelines, which would have led to a lower survival rate. This is discussed further in the section below on older women. Also, women under 40 years may have been given more aggressive treatment than the guidelines indicated. For young women, it may therefore be the opposite, that is, they may have been treated more actively using, for example, chemotherapy, and their survival rate may have been even lower if we had been able to adjust for treatment.
In the present study, young age (<40 years) was positively associated with high BCSM following invasive breast cancer. In the second diagnostic period (1971 to 1980) the BCSM of young women decreased and then increased again in the following diagnostic period (1981 to 1991). However, it is difficult to interpret these small changes in BCSM as only 44 women under 40 years were diagnosed in the second period and chance may have caused some of the change.
It has been shown that young women have higher grade tumors, which are consequently more aggressive [8,22,23]. Tumors in young women are also more prone to be hormone receptor negative, which makes them less susceptible to respond well to adjuvant endocrine therapy such as tamoxifen [8,23]. Therefore the medical adjuvant therapy form for young women has instead been chemotherapy (introduced in the late 1970s at this institution) . However, according to the results of this study, the BCSM of young women did not decrease in relation to other age groups in spite of the introduction of chemotherapy. Young women had the second highest BCSM in the diagnostic period 1981 to 1991, following the introduction of chemotherapy.
Several previous studies have also found young women to have a higher BCSM than other age groups [6-10,13,24-29]. However, two studies concluded that there was no difference in survival rates between young and middle-aged women [14,30]. The contradictory results may be due to breast cancer being a heterogeneous disease, with the prognostic factor age only having an effect in certain subgroups of breast cancers, such as the stage factors size, ALNI, and distant metastasis. A few previous studies have stratified for stage to evaluate this, with contradictory results. One study reported worse survival rates for young women in stages I and II , one large study for stages I to III , and one review from 2008 concluded that a worse outcome for young women is found in all stages (I to IV) .
Our analysis, stratified for ALNI, demonstrated that the RR increase of young women was especially apparent in ALNI-negative young women; ALNI-negative women aged under 40 years had a worse prognosis than ALNI-negative women in other age categories. As ALNI status is the most important prognostic factor and women who are diagnosed as ALNI-negative are expected to have a favorable prognosis, this is an important finding. A reason for our result could be that the strong confounding factor ALNI had been stratified for, which may reveal a relatively weak prognostic factor; young age. It can also be because adjuvant treatments, such as radiotherapy, chemotherapy, and endocrine treatment, were given mainly to ALNI-positive women . Consequently, the outcome in ALNI-negative women would reveal the natural course of events, where young women were distinguished as having the very worst five-year prognosis out of all age groups. In line with these findings, a previous study has shown the poor prognosis of young women is only to be found in those not treated with adjuvant therapy .
In the sensitivity analysis, there was no large difference in BCSM rate between women under 35 years and 35 to 39 years. However, the number of women diagnosed who were under 35 years was small (53 women), hence the statistical power of the analysis was poor.
Middle-aged women (50 to 69 years) had a worse survival rate than the reference group (40 to 49 years) in the first two diagnostic periods. However, in the last diagnostic period, starting in 1981, women aged 50 to 59 years had a similar survival rate and women aged 60 to 69 years had an even better survival rate, as compared to the reference group. Mammographic screening was introduced at this institution in 1976 in a randomized trial, inviting 50% of women aged 45 to 69 to participate . We did not have information on which of the breast cancer cases were detected by mammographic screening. However, it is possible to hypothesize that this may explain some of the decrease in BCSM over the diagnostic periods, seen in women aged 50 to 59 years and 60 to 69 years in this study, as they would have been diagnosed at an earlier stage and subsequently have had a longer time from diagnosis until potential death from breast cancer (a lead time effect) . On the contrary, the youngest and oldest women may still have experienced a relatively late diagnosis and, hence, a continuing higher BCSM rate. Adjuvant therapy was also introduced in the late 1970s. This may also be part of improved survival rates for middle-aged women due to the connection in time.
Women aged 70 to 79 years had a high BCSM until the last diagnostic period. It may be that diagnosis and treatment improved also for this age category, but slightly later than for middle-aged women.
The strongest association for all age categories was for the oldest women (≥80 years), who had a worse outcome in all analyses. Previous studies have found contradictory results, with old age being shown to be associated with [5,12,13,32], as well as not associated with [4,14] a high mortality rate. One large study even found elderly women with ALNI-negative tumors to have a favorable outcome . Adjustment for stage at diagnosis made the association slightly weaker in the present study, suggesting the possibility of delayed diagnosis. However, the results still remained statistically significant following adjustment for stage. Furthermore, stratification for ALNI did not have a large effect; therefore stage could not explain the entire difference in BCSM rate.
The survival rate for elderly women improved over the diagnostic periods. A reason for this may be that tumors in elderly women are often hormone receptor positive . Hence a high percentage of this age group responds well to endocrine therapy [33,34]. The endocrine therapy tamoxifen was introduced in 1978 at this institution and could have contributed to this improved survival rate .
Although the survival rate improved for elderly women over the diagnostic periods, elderly women continued to have a higher relative risk when compared to other age categories. This could be due to elderly women potentially not receiving treatment according to the guidelines. In this material we unfortunately did not have access to data on adjuvant therapy, but we did have information on type of operation and data on whether or not an axillary dissection was performed. This indeed showed that it was more common that older women had been regarded as unsuitable for surgery and an axillary dissection was also less common in these women. Furthermore, it has been displayed in previous studies that women have not received treatment according to the guidelines, especially regarding adjuvant radiotherapy [12,15,35-38]. Other studies have also shown axillary lymph node dissection to be less frequently performed in the elderly [5,36,38]. Comorbidity can naturally lead to elderly women receiving less aggressive treatment, but studies have shown that old age is an independent risk factor for not receiving appropriate therapy after control for comorbidity .