Breast cancer mortality as a function of age

Introduction

As life expectancy in the US has steadily increased up until prior to the COVID-19 pandemic [1], trends in incidence of BC, particularly the estrogen receptor (ER) positive subtypes, are similarly following as a consequence of aging [2]. While BC remains the most highly incident cancer diagnosed in US women, the female BC death rate has declined significantly over the preceding years [3]. The overall survival of elderly women with BC is predictably worse to that of younger counterparts given higher rates of comorbidities and frailty due to older age. However, when evaluating BC specific survival (BCSS), elderly patients have significantly better outcomes yet with the youngest patients demonstrating the worst BCSS rates [4].

Lower BC-associated mortality in the elderly is notable considering challenges faced with providing aggressive standard of care therapies when limited by performance status and frailty measures, suggesting the development of relatively more indolent disease in the elderly with a less aggressive course. Congruently, multiple studies have characterized BCs in younger patients with higher histological grade, larger size, low or absent expression of ER and/or progesterone receptors (PR), and greater lymph node (LN) positivity [5–10]; while LN positivity in patients with early stage disease is found to be decreased with increasing age [11].

To gain insight into the relative lethality of BC in women diagnosed at younger versus older ages, we sought to compare mortality rates among BC patients as compared to mortality rates in the general population, matched by age and race (i.e., observed vs. expected mortality). With the presumption that BCs diagnosed at younger ages represent a more severe clinical entity from disease diagnosed at older ages, a larger differential in observed to expected mortality was postulated in younger women diagnosed with BC. In contrast, in elderly patients with BC, we hypothesized little to no difference in observed to expected mortality due to a potentially less aggressive disease course, coupled with overall high competing (non-BC) causes of mortality in older women with and without BC.

Methods

Results

Among 52,509 patients, respective numbers of patients by age group were: 20 to 44 years (n = 5,589; 10.6%), 45 to 55 years (n = 12,499; 23.8%), 56 to 69 years (n = 19,035; 36.3%), and 70 to 90 years (n = 15, 386; 29.3%). Ninety-two percent or more of patients were of white race across the 4 age groups (Table 1). With increasing age, the proportion of patients with white race increased with a corresponding decrease in patients of black race. As expected, co-morbidity rates were significantly more frequent, as were rates of selected medication use with increasing age. In addition, we found that mean vitamin D levels were progressively higher across age groups (Table 1).

Inflammation is associated to aging mechanisms and cancer development [19]. The NLR and the SII are biomarkers used to indirectly investigate the influence of inflammation with cancer prognosis [20, 21]. In this regard, higher NLR ratios and SII index are in some studies associated with poorer survival. We therefore analyzed these parameters in our cohort and found that with increased age, more patients had NLRs >6.0. The SII was nominally higher among women <55 years of age, although a linear trend with higher SII values as women aged was not observed (Table 1).

The AJCC stage of BC was not available in the records (undetermined status) in about a quarter of all patients. Removing women with undetermined status, the respective percentages of women with Stage 0/1 disease across the 4 age groups were 54.4%, 67.1%, 71.4%, and 69.1% (p < 001). The youngest group (ages 20–44) had overall higher stages of BC, although elderly women (ages 70–90) had the highest prevalence of stage 4 disease at presentation. Women in the elderly age group were also more likely to have intermediate grade II BC as compared to the other age groups (Table 2). Similarly, women in the elderly group were more likely to be diagnosed with lower tumor grade and well-differentiated tumors. Youngest women were more likely to have larger tumor size and regional LN involvement upon diagnosis (p < 0.001). Elderly women were more likely to be diagnosed with T4 than other age groups (p < 001) (Table 2). As women aged, they were less likely to have regional LN involvement. The prevalence of tumor hormone receptor positivity was estrogen receptor (ER) negative (total n = 31,852; 16.4%), human epidermal growth factor receptor 2 (HER2) negative (total n = 15,662; 85.0%), progesterone receptor (PR) negative (total n = 31,686; 25.5%), and triple negative (total n = 52,509; 7.9%). Younger women (<45 years) were more likely to have ER negative and Her2 positive tumors (Table 2).

Fifty-one percent of women 20–44 years had one or more LN’s removed which was significantly higher than all other age groups (Table 3). Younger women were also more likely to have received chemotherapy regardless of stage at diagnosis and tumor grade (Supplementary Table 2), and less likely to have received hormone therapy (p < 0.001). The elderly group was least likely to have received radiation treatment (p < 001).

SMRs of all-cause mortality after BC diagnosis were determined by age group and are reported in Supplementary Table 3, with cases limited to Stage 0/1 disease listed in Supplementary Table 4. Notably higher SMRs occurred in BC patients aged 20 to 44 years, with a peak of 11.78 at 5 years post diagnosis compared to 4.60 in the age 45 to 55 cohort, 2.48 in the age 56 to 69 cohort, and lowest at 1.58 in ages 70 to 90 (Figure 1, solid lines). Similar trends of decreasing SMRs as age increased were observed when the analysis was limited to patients diagnosed with Stage 0/1 disease (Figure 1, dashed lines). In patients diagnosed with Stage 0/1 disease, trend towards an SMR <1 was observed at 1-year follow-up for all cohorts. The SMR remained significant at <1 at 3- and 5-year follow-up for patients aged 70 and older, with 10-year mortality rates reaching an SMR similar to the general population (Figure 1A–1D, Supplementary Table 4), likely due to age-related natural death.

Rates of 5-year overall survival were similar in patients <70 years of age, whereas women diagnosed at ages 70 to 90 years had worse 5-year overall survival outcomes compared to the rest of age groups. We also found that rates of 5-year BC recurrence were similar in patients aged ≥45 years, while women diagnosed at ages 20 to 44 years (Figure 2) had higher recurrence rates than the other age groups. In Cox regression models stratified by age (Table 4), factors independently associated with worse 5-year mortality among women diagnosed at age 20 to 44 years included: HER2 negative BC, tumor grades 2 and 3, stage 2 or higher disease, and regional LN metastases (all hazard ratios >2.3). The adjusted hazard ratio (HR) of 5-year mortality by age for women diagnosed at age 20 to 44 years with HER2 negative BC (HR = 2.63; 95% CI: 1.46 to 4.74) was markedly higher than for women diagnosed at age 45 to 55 years (HR = 1.67; 95% CI: 1.18 to 2.36), 56 to 69 years (HR = 1.67; 95% CI: 1.26 to 2.21), and 70 to 90 years (HR = 1.06; 95% CI: 0.86 to 1.30). Similarly, the adjusted hazard ratio (HR) for women diagnosed at age 20 to 44 years for tumor grade 3 (HR = 7.22; 95% CI: 2.29 to 22.78) was substantially higher than for women diagnosed at age 45 to 55 years (HR = 2.52; 95% CI: 1.64 to 3.85), 56 to 69 years (HR = 1.37; 95% CI: 1.12 to 1.67), and 70 to 90 years (HR = 1.37; 95% CI: 1.20 to 1.55).

Among patients who died within 10 years of diagnosis, recurrence rates are significantly higher in the cohort of patients aged 20–44 and gradually decreasing with age. While this precludes definitive conclusions regarding breast cancer specific survival, the higher rates of recurrence seen in the younger cohort implies higher mortality rates due to presence of disease as compared to patients aged 70–90 who died within 10 years that had substantially lower recurrence rates and thus mortality more likely secondary to other comorbidities and/or age-related mortality (Supplementary Figure 1).

Discussion

Incidence of BC is expected to rise by 50% by 2050 [22]. It is expected that these increased rates will be reflected primarily among post-menopausal women aged 70–84, particularly in those with ER+ disease, due to a better overall survival in the aging population [2]. An enhanced understanding of the underlying biological processes in elderly BC is critical to delineate the role of therapeutic intervention in this population with increased frailty.

In this study, we show better observed to expected mortality rates for BC patients as age increases, and an apparent more favorable 5-year all-cause mortality risk (SMR <1) in patients diagnosed with early-stage disease (AJCC Stage 0/1) after the age of 70 as compared to the general population. Prior work from twenty years ago demonstrated similar trends in observed to expected mortality rates as a function of age with a SEER-derived matched control group from the general population [15]. It is noteworthy that these mortality observations remain stable in despite advances in BC treatment over the past two decades. This may suggest that there may be an underlying biology of BC in aging women that is unchanged by therapeutic advances.

Our results show that black women are diagnosed with BC earlier in life as compared to white women. This dual distribution of BC diagnosis by age and race was in conjunction with a prior study [23], where non-white women (including Hispanic and Asian) also tended to present with more advanced disease at diagnosis than white women [23]. These differences may be due to higher genomic and biologic tumor heterogeneity including basal-like features, and/or socioeconomical disparity among the non-white population [24, 25].

We report progressively decreasing SMR with each increasing decade of age of BC diagnosis. This effect is maintained even when limiting analysis to in situ and early-stage disease (Stage 0/1). Surprisingly, with a stage 0/1 BC diagnosis in women between the ages of 70–90 the SMR remained lower than 1, indicating a survival advantage with BC diagnosis, heralding an association to a likely protective effect with tumor development that is in sharp contrast to the effect of diagnosis in younger women. A trend to SMR<1 noted for all ages of patients with Stage 0/1 disease at 1-year follow-up is likely attributed to closer medical monitoring and access to care in the early timeframe status post cancer diagnosis. Collectively, our data support the presence of a differential clinical entity with an inherently disparate biology observed in elderly patients with BC.

As described, SII and NLR are proposed to be prognostic in many tumor subtypes and may reflect underlying host immunity (27–29). In our study, the highest SII were in our pre-menopausal cohorts (ages 20–44 and 45–55). More importantly, elderly patients had more frequently NLRs >6. The presence of increased NLRs as women age may suggest the presence of evolving immune profiles underlying the development of BC. This may influence the disease phenotype as women age and could influence the decreased SMR <1 at five years seen in our 70–90-year age cohort with early-stage disease [26–28].

Additionally, we report that 5-year survival rates were worse in the 70–90 age group compared to younger women. Recurrence rates of women aged 20–44 were also higher compared to women ≥45 years of age; both findings were in line with prior reports [29–31]. As seen in the present study and discussed previously, underlying comorbidities and less invasive treatments may partly explain the higher mortality found in the 70–90 age group [29]. Higher rates of recurrence among younger women could be explained by the higher percentage of ER-/PR- tumors, decreased BC awareness at younger ages and the presence of familial mutations [31].

Limitations of our analysis include the retrospective data collection (i.e., data were not collected for research purposes), and missing data in some patients on cancer staging, tumor characterization, disease progression, and hormone receptor status. In addition, our results are from a single heath care system which precludes generalizability to the US population at large. We were also unable to discern cause of death, and therefore could not evaluate BC-specific mortality. Finally, the 30-year period of data collection (1990 to 2020) has included a large percentage of patients who were treated decades ago prior to more recent advances in the treatment of BC.

In summary, we report data indicative of a more indolent disease in BC patients with advanced age. Women with early breast cancer diagnosed at ages 70 and older had better overall 5-year survival rates than the general population, as demonstrated by low SMRs (<1). These findings suggest that BC in the elderly could be inherently different from the more clinically aggressive disease observed in younger patients. While the development of BC significantly worsens the observed to expected mortality of younger women, it may potentially serve as a factor linked to better survival in the elderly, especially in cases where stage 0/1 BC is diagnosed. Further studies are needed to better understand the underlying cues of these findings.

Supplementary Materials

Supplementary Figure 1

Supplementary Table 1

Supplementary Tables