Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. ...Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14(+)HLA-DR(low/-)CD86(low/-)CD80(low/-)CD163(low/-)) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.
Epidemiologic studies indicate that dietary factors, such as coffee, may influence breast cancer and modulate hormone receptor status. The purpose of this translational study was to investigate how ...coffee may affect breast cancer growth in relation to estrogen receptor-α (ER) status.
The influence of coffee consumption on patient and tumor characteristics and disease-free survival was assessed in a population-based cohort of 1,090 patients with invasive primary breast cancer in Sweden. Cellular and molecular effects by the coffee constituents caffeine and caffeic acid were evaluated in ER(+) (MCF-7) and ER(-) (MDA-MB-231) breast cancer cells.
Moderate (2-4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER(+) tumors (Ptrend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER(+) tumors (adjusted HR, 0.51; 95% confidence interval, 0.26-0.97). Caffeine and caffeic acid suppressed the growth of ER(+) (P ≤ 0.01) and ER(-) (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER(+) cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER(+) and ER(-) cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death.
The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER(+) and ER(-) breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth.
Clinical cancer trials are crucial for the implementation of new treatments in the clinical setting, but it is equally crucial that patients are given the opportunity to make a well-informed decision ...about participation. The inclusion process is complex, including both oral and written information about the trial. The process of patients' decision-making regarding clinical cancer trials has not yet been sufficiently studied. This interview study aims to explore the process of patients' reasoning regarding the decision to participate in a clinical cancer trial.
The study is based on 27 individual face-to-face interviews with patients who had decided to participate in a clinical cancer trial. The interviews were audio-recorded and transcribed verbatim and then analysed using inductive content analysis.
Content analysis revealed 17 subthemes grouped into five themes: (1) an unhesitating decision to participate; (2) a decision based on flimsy grounds and guided by emotion; (3) feeling safe and secure with my decision; (4) faced with a choice versus what choice do I have? and (5) hoping for help while helping others. The decision to participate in a clinical cancer trial was often immediate and guided by emotions, based on a trusting relationship with healthcare personnel rather than on careful reading of written information. Palliative patients, in particular, sometimes had unrealistic beliefs about the effectiveness of the trial treatment.
It is vital that the decision to participate in a clinical cancer trial is preceded by an honest dialogue about possible positive and negative effects of the trial treatments, including other options such as supportive care in the palliative setting. Our findings also raise the questions of how important written information is for the decision-making process and also whether genuine informed consent is possible. To reach a higher degree of informed consent, it is most important that the oral information is given in a thorough and unbiased manner.
To evaluate whether tumor androgen receptor (AR) expression was prognostic and/or predictive for endocrine treatment alone or in combination with estrogen receptor (ER). The AR has been hypothesized ...to have differential prognostic roles in breast cancer depending on tumor ER status, and to influence endocrine treatment response.
A population-based prospective cohort of 1,026 patients diagnosed with primary invasive breast cancer in Lund, Sweden, between 2002 and 2012 was followed until June 2014. Associations between immunohistochemical AR expression in tumor tissue microarrays, patient and tumor characteristics, and AR genotypes were analyzed. Disease-free survival (DFS) by AR status, and combined ER/AR status was assessed in various treatment groups.
AR expression was assessable in 913 tumors. AR(+) tumors (85.0%) were associated with higher age (P = 0.036) and favorable tumor characteristics. The AR(+) status was a prognostic marker for DFS (LogRank P = 0.025). There was an interaction between AR and ER expression with respect to prognosis (adjusted P(interaction) ≤ 0.024). Tumors with discordant hormone receptor expressions (ER(+)AR(-) or ER(-)AR(+)) demonstrated worse prognosis compared with concordant tumor expressions (ER(+)AR(+) or ER(-)AR(-)) in multivariable models adjusted HRs (95% confidence intervals); ≥ 1.99 (1.28-3.10), P ≤ 0.002. ER(+)AR(-) indicated early treatment failure with aromatase inhibitors (AI) among chemonaïve patients aged 50 or older.
Prediction of breast cancer prognosis and treatment response was improved by combining AR and ER status. AR negativity predicted early treatment failure with AI but not tamoxifen, a finding that warrants confirmation in a randomized setting. Patients may benefit from anti-androgens or selective AR modulators.
Purpose
The increase in clinical trials with androgen receptor (AR)-targeting drugs emphasizes the need of clarifying the role of AR expression in different breast cancer subtypes. AR confers good ...prognosis in estrogen receptor positive (ER+) breast cancer, but its role in ER-negative (ER−) breast cancer is unclear. The aim of this study was to elaborate on previous findings of a differential prognostic role for AR depending on ER status, using breast cancer mortality (BCM) as endpoint, in a population-based cohort from the Malmö Diet and Cancer Study.
Methods
Immunohistochemical AR expression was assessed in 910 women with invasive breast cancer diagnosed 1991–2010, supplemented with clinicopathological information, vital status, and cause of death, with the last follow-up in December 2014 (median 10 years). Survival analyses according to AR status and AR/ER combinations were performed.
Results
AR expression was available for 671 tumors. AR+ (
n
= 573, 85%) was associated with favorable established tumor markers and lower BCM in univariable analysis, especially during the first 5 years following diagnosis HR 0.4; 95% confidence intervals (CI) 0.2–0.7. Multivariable analysis for short-term follow-up indicated higher BCM among patients with AR+ER− tumors (HR 3.5; 95% CI 1.4–9.1) than other AR and ER combinations.
Conclusions
AR expression added prognostic information to ER expression with respect to short-term prognosis. The worst prognosis was seen for patients with AR+/ER− tumors in short-term follow-up, supporting the pre-specified hypothesis. However, larger cohorts are needed for further characterization of the role of AR expression in ER− breast cancer.
Purpose
Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master ...regulator of membrane transport and cell signaling. Several
CAV1
SNPs have been linked to multiple cancers, but the prognostic impact of
CAV1
SNPs in breast cancer remains unclear. Here, we investigated
CAV1
polymorphisms in relation to clinical outcomes in breast cancer.
Methods
A cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six
CAV1
SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction.
CAV1
genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments).
Results
Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The
CAV1
rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HR
adj
) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HR
adj
2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome.
Conclusion
CAV1
polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.
27-Hydroxycholesterol (27HC) stimulates estrogen receptor-positive (ER+) breast cancer (BC) progression. Inhibiting the sterol 27-hydroxylase (CYP27A1) abrogates these growth-promoting effects of ...27HC in mice. However, the significance of CYP27A1 expression on BC biology and prognosis is unclear.
Intratumoral CYP27A1 expression in invasive BC was measured by immunohistochemistry in two Swedish population-based cohorts (n = 645 and n = 813, respectively). Cox proportional hazards models were used to evaluate the association between CYP27A1 expression and prognosis.
CYP27A1 was highly expressed in less than 1/3 of the tumors. High CYP27A1 expression was more frequent among high-grade tumors lacking hormone receptor expression and with larger tumor sizes. Over a median of 12.2 years follow-up in cohort 1, high CYP27A1 expression was associated with impaired survival, specifically after 5 years from diagnosis among all patients overall survival (OS), HR
= 1.93, 95%CI = 1.26-2.97, P = 0.003; breast cancer-specific survival (BCSS), HR
= 2.33, 95%CI = 1.28-4.23, P = 0.006 and among patients ≥ 55 years presenting with ER+ tumors OS, HR
= 1.99, 95%CI = 1.24-3.21, P = 0.004; BCSS, HR
= 2.78, 95%CI = 1.41-5.51, P = 0.003. Among all patients in cohort 2 (median follow-up of 7.0 years), CYP27A1 expression was significantly associated with shorter OS and RFS in univariable analyses across the full follow-up period. However after adjusting for tumor characteristics and treatments, the association with survival after 5 years from diagnosis was non-significant among all patients OS, HR
= 1.08, 95%CI = 0.05-2.35, P = 0.83 and RFS, HR
= 1.22, 95%CI = 0.68-2.18, P = 0.50 as well as among patients ≥ 55 years presenting with ER+ tumors OS, HR
= 0.46 95% CI = 0.11-1.98, P = 0.30 and RFS, HR
= 0.97 95% CI = 0.44-2.10, P = 0.93.
CYP27A1 demonstrated great potentials as a biomarker of aggressive tumor biology and late lethal disease in postmenopausal patients with ER+ BC. Future studies should investigate if the benefits of prolonged endocrine therapy and cholesterol-lowering medication in BC are modified by CYP27A1 expression.
Accumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; ...however, the relationship between statin use and patterns of breast cancer recurrence remains unclear.
We identified all Malmö Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users.
The final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in non-users. Statin use was associated with a reduced risk of breast cancer recurrence (HRadj = 0.88 95% CI: 0.82–0.96). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HRadj = 0.86 95% CI: 0.80–0.94) but not loco-regional recurrence (HRadj = 0.97 95% CI: 0.87–1.08).
In the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelial-mesenchymal transition.
•Breast cancer patients using statins have fewer recurrences.•Post-diagnosis statin use specifically reduced the risk of distant recurrence.•No protection against loco-regional recurrences was observed.
Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral ...glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82-0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.
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