Ten-Year Mortality after a Breast Cancer Diagnosis in Women with Severe Mental Illness: A Danish Population-Based Cohort Study

<div><p>Background</p><p>Breast cancer is the leading cause of cancer death in women worldwide. Nevertheless, it is unknown whether higher mortality after breast cancer contributes to the life-expectancy gap of 15 years in women with severe mental illness (SMI).</p><p>Methods</p><p>We estimated all-cause mortality rate ratios (MRRs) of women with SMI, women with breast cancer and women with both disorders compared to women with neither disorder using data from nationwide registers in Denmark for 1980–2012.</p><p>Results</p><p>The cohort included 2.7 million women, hereof 31,421 women with SMI (12,852 deaths), 104,342 with breast cancer (52,732 deaths), and 1,106 with SMI and breast cancer (656 deaths). Compared to women with neither disorder, the mortality was 118% higher for women with SMI (MRR: 2.18, 95% confidence interval (CI): 2.14–2.22), 144% higher for women with breast cancer (MRR: 2.44, 95% CI: 2.42–2.47) and 327% higher for women with SMI and breast cancer (MRR: 4.27, 95% CI: 3.98–4.57). Among women with both disorders, 15% of deaths could be attributed to interaction. In a sub-cohort of women with breast cancer, the ten-year all-cause-mortality was 59% higher after taking tumor stage into account (MRR: 1.59, 95% CI: 1.47–1.72) for women with versus without SMI.</p><p>Conclusions</p><p>The mortality among women with SMI and breast cancer was markedly increased. More information is needed to determine which factors might explain this excess mortality, such as differences between women with and without SMI in access to diagnostics, provision of care for breast cancer or physical comorbidity, health-seeking-behavior, and adherence to treatment.</p></div

All-cause mortality and breast-cancer-specific mortality.

<p>All-cause mortality and breast-cancer-specific mortality.</p

All-cause mortality rates (MRs) as a function of age for women with SMI only, women with breast cancer only, women with SMI and breast cancer, and women with neither of the two disorders (Denmark, 1980–2011).

<p>Abbreviations: MR: mortality rate; SMI: severe mental illness; BC: breast cancer; Reference: women from the general population with neither of the two disorders.</p

Mortality rate ratios (MRRs) for women with SMI, women with breast cancer and women with both SMI and breast cancer compared to women with neither SMI nor breast cancer in Denmark in 1980–2012 (N = 2,665,963).

<p>Mortality rate ratios (MRRs) for women with SMI, women with breast cancer and women with both SMI and breast cancer compared to women with neither SMI nor breast cancer in Denmark in 1980–2012 (N = 2,665,963).</p

Ten-year all-cause MRRs for women with SMI and breast cancer compared to women with breast cancer only.

<p>Abbreviations: MRR: mortality rate ratio; MR: mortality rate; CI: confidence interval; CCI score: Charlson Comorbidity Index score (excluding cancers). The MRRs were adjusted for age and calendar period. ^aEach death is assigned to the category at the time of death (for example, the number of deaths are counted for each calendar period category at the time of death: if a person died in 1981, this death will be assigned to the calendar period category 1980–1983). ^bNumber of deaths are counted for each tumor stage category at the time of diagnosis.</p

Impact of age, intrinsic subtype and local treatment on long-term local-regional recurrence and breast cancer mortality among low-risk breast cancer patients

<p><b>Aim:</b> To evaluate the long-term prognostic impact of age, local treatment and intrinsic subtypes on the risk of local-regional recurrence (LRR) and breast cancer mortality among low-risk patients.</p> <p><b>Material and methods:</b> Cohort study with prospectively collected data, balanced five-year age groups, including 514 Danish lymph node negative breast cancer patients diagnosed between 1989 and 1998, treated with mastectomy (N = 320) or breast-conserving therapy (BCT) (N = 194) and without systemic treatment. Intrinsic subtype approximation was performed by combining information on estrogen-, progesterone-, HER2 receptor and Ki67.</p> <p><b>Results:</b> The majority of the tumors had a luminal subtype: 70% Luminal-A (LumA), 16% Luminal-B (LumB), and 10% Luminal-HER2 + (Lum-HER2+). The distribution of intrinsic subtypes between younger (≤45 years) and older (>45 years) patients was similar. Intrinsic subtypes had no prognostic impact on the 20-year LRR risk, regardless of age. A distinct 20-year mortality pattern was observed among the younger patients: 11% of patients with LumB tumor died of breast cancer within the first five years after primary surgery, 23% of patients with Lum-HER2+ tumor died within a 5–10-year period, whereas patients with LumA tumor died with a constant low rate throughout the 20-year period. After 20 years of follow-up, patients with LumA tumor had breast cancer mortality comparable to that of patients with LumB tumor (20%) and lower than Lum-HER2+ tumor (39%). Among the older patients, no distinct mortality pattern was observed, and the 20-year breast cancer mortality was not associated with intrinsic subtypes.</p> <p><b>Conclusion:</b> Among low-risk patients, 96% of the tumors were Luminal and the distribution of intrinsic subtypes between younger (≤45 years) and older (>45 years) patients was similar. The observed higher frequency of LRR among younger low-risk BCT patients was not associated intrinsic subtype. The 20-year breast cancer mortality was non-significant for LumA tumors among the older patients, whereas among the younger patients, LumA tumors had a comparable mortality with LumB, but lower than for Lum-HER2 + tumors.</p

Verification of neutrophil-depletion in CDF1 and C3H/HeN mice.

<p>A) Granulocytes (percentage of leucocytes) in non-tumor bearing CDF1 mice as a function of hours after treatment (n = 5). The mice were treated with PBS (○), the anti-neutrophil antibody 1A8 (•), CA4P (25 mg/kg, ▿), 1A8 and CA4P (25 mg/kg) in combination (▴), CA4P (250 mg/kg, □), or 1A8 and CA4P (250 mg/kg) in combination (▪). B) Granulocytes as a percentage of leucocytes in C3H/HeN mice 24 h after injection of PBS, 1A8, CA4P (25 mg/kg), or 1A8 and CA4P in combination (n = 5). The data is presented as median values and error bars represent the 25^th and 75^th percentiles.</p

In vitro CA4P toxicity assay.

<p>A) <i>In vitro</i> effect of 2 h incubation of whole blood in the presence of CA4P (10 µM), CA4 (10 µM), DMSO diluted in saline, or saline on the percentage of apoptotic or dead granulocytes. Data is presented as mean + SEM (n = 3). B) A representative forward-side scatter demonstrating gating of the granulocytes (the pink oval gate). C) Verification of Gr-1 positivity of cells in the granulocyte gate. The red line shows the isotype control and the blue line represents the granulocytes. D–H) Annexin V (expressed by apoptotic cells) and 7AAD (expressed by dead cells) expression in granulocytes from D) a negative control (no 7AAD or annexin V staining), or after incubation with E) saline, F) DMSO, G) CA4, or H) CA4P.</p

Effect of neutrophil depletion on CA4P-mediated necrosis.

<p>1A8: anti-neutrophil antibody, CA4P: Combretastatin A-4 disodium phosphate.</p><p>*signifcantly different from the control group,</p><p>*′significantly different from the 1A8 group. Values are mean ± SEM (n = 5–21).</p><p>Effect of neutrophil depletion on CA4P-mediated necrosis.</p

The effect of CA4P treatment on cytokine levels in C3H mammary carcinomas in CDF1 mice.

<p>A) VEGF, B) MIP-1α (CCL3), C) KC (CXCL1), and D) MIP-2 (CXCL2) concentration in tumors as a function of hours after treatment with 25 mg/kg CA4P and in tumors from saline-treated mice. A) and C) Data is presented as mean ± SEM. B) and D) Data is presented as the median (horizontal bar), the 25^th and 75^th percentile (bottom and top of boxes) and the 10^th and 90^th percentiles (error bars). For all data n = 10.</p