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Background: Extended, more effective breast cancer treatments have increased the prevalence of long-term survivors. We investigated the risk of late breast cancer recurrence (BCR), 10 years or more after primary diagnosis, and associations between patient and tumor characteristics at primary diagnosis and late BCR up to 32 years after primary breast cancer diagnosis.Methods: Using the Danish Breast Cancer Group clinical database, we identified all women with an incident early breast cancer diagnosed during 1987-2004. We restricted to women who survived 10 years without a recurrence or second cancer (10-year disease-free survivors) and followed them from 10 years after breast cancer diagnosis date until late recurrence, death, emigration, second cancer, or December 31, 2018. We calculated incidence rates per 1000 person-years and cumulative incidences for late BCR, stratifying by patient and tumor characteristics. Using Cox regression, we calculated adjusted hazard ratios for late BCR accounting for competing risks.Results: Among 36 924 women with breast cancer, 20 315 became 10-year disease-free survivors. Of these, 2595 developed late BCR (incidence rate = 15.53 per 1000 person-years, 95% confidence interval = 14.94 to 16.14; cumulative incidence = 16.6%, 95% confidence interval = 15.8% to 17.5%) from year 10 to 32 after primary diagnosis. Tumor size larger than 20 mm, lymph node-positive disease, and estrogen receptor-positive tumors were associated with increased cumulative incidences and hazards for late BCR.Conclusions: Recurrences continued to occur up to 32 years after primary diagnosis. Women with high lymph node burden, large tumor size, and estrogen receptor-positive tumors had increased risk of late recurrence. Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches. [ABSTRACT FROM AUTHOR]

Background: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence.Methods: In this population-based case-control study, we included women diagnosed with stage I-III breast cancer between 1985 and 2001, aged 35-69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER-/TAM-). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence.Results: HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER-/TAM- stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER-/TAM- OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER-/TAM- stratum.Conclusion: In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER- breast cancer. [ABSTRACT FROM AUTHOR]

Background: Statins treat hyperlipidemia and prevent cardiovascular morbidity and mortality. Evidence suggests that they also have anti-neoplastic activity. Several studies show a reduced rate of breast cancer recurrence among lipophilic statin users (e.g., simvastatin), motivating calls for clinical trials of statins in breast cancer patients. We measured the impact of genetic variation in statin-metabolizing enzymes and drug transporters on the recurrence rate in simvastatin-treated breast cancer patients. Methods: We conducted a nested case-control study among Danish women diagnosed with non-metastatic, invasive breast cancer between 2004–2010 who had filled ≥1 prescription for simvastatin after diagnosis. Cases were all breast cancer recurrences from the source population; one control was matched to each case on cancer stage, estrogen receptor and hormone therapy status, calendar period of diagnosis, and duration of simvastatin exposure. We genotyped variants in simvastatin-metabolizing enzymes (CYP3A4/rs35599367 and CYP3A5/rs776746) and drug transporters (ABCB1/rs2032582 and SLCO1B1/rs4149056), and estimated their association with recurrence with logistic regression models. Results: We observed protective (though imprecisely-measured) associations between variants in genes encoding drug transporters (ABCB1 and SLCO1B1) and simvastatin-metabolizing enzymes (CYP3A4 and CYP3A5) and breast cancer recurrence in simvastatin-treated women. For example, carrying two variant alleles in ABCB1 was associated with a 31% lower rate of recurrence (multivariable OR = 0.69, 95% CI: 0.31, 1.5). Conclusion: Our study provides weak evidence to support the use of genetic variation in ABCB1, SLCO1B1, CYP3A4, and CYP3A5 as biomarkers of breast tumor response to simvastatin. Validation of these findings within adjuvant clinical trials is encouraged. [ABSTRACT FROM AUTHOR]

Background: Survivin is an inhibitor of apoptosis, and its expression associates with poor outcomes in multiple cancers. It may be a therapeutic target due to its unique expression in cancer cells. Methods: We estimated the association between nuclear and cytoplasmic survivin expression in primary tumors and breast cancer recurrence. In this case-control study, we included women age 35-69, diagnosed with stage I-III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Group. We identified 541 patients with breast cancer recurrence with estrogen receptor-positive disease who were treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 with estrogen receptor-negative carcinomas, not treated with tamoxifen, and who survived at least 1 year (ER−/TAM−). Controls were matched to cases on ER/TAM status, date of surgery, menopausal status, stage and county. Survivin expression was estimated by immunohistochemistry on tissue microarrays. We fit logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associating nuclear and cytoplasmic survivin expression with recurrence. Results: Associations between nuclear and cytoplasmic survivin expression and breast cancer recurrence were near-null in both ER+/TAM + and ER−/TAM − strata. For the cytoplasmic to nuclear ratio (CNR) of survivin expression, we found a null association in the ER+/TAM + group comparing CNR ≥5 with CNR <5, but an association (OR =2.48, 95% CI: 1.15, 5.31) in the ER−/TAM − group. Conclusions: Survivin expression was not associated with breast cancer recurrence in this study. The CNR ratio may warrant further investigation especially among ER − tumors. [ABSTRACT FROM AUTHOR]

Background: Myriad reports suggest that frequently used prescription drugs alter the viability of breast cancer cells in pre-clinical studies. Routine use of these drugs, therefore, may impact breast cancer prognosis, and could have important implications for public health. Methods: The Danish Breast Cancer Group (DBCG) clinical database provides high-quality prospectively collected data on breast cancer diagnosis, treatment, and routine follow-up for breast cancer recurrence. Individual-level linkage of DBCG data to other population-based and medical registries in Denmark, including the Danish National Prescription Registry, has facilitated large population-based pharmacoepidemiology studies. A unique advantage of using DBCG data for such studies is the ability to investigate the association of drugs with breast cancer recurrence rather than breast cancer mortality – which may be misclassified – or all-cause mortality. Here we summarize findings from pharmacoepidemiological studies, based on DBCG data, on the association between routinely used prescription drugs and risk of breast cancer recurrence. Results: Our findings suggest that concurrent use of glucocorticoids, ACE inhibitors, aspirin, NSAIDs, selective COX-2 inhibitors, digoxin, and opioids has little impact on breast cancer recurrence. Similarly, patients who use SSRIs concurrently with tamoxifen treatment are not at increased risk of recurrence. In contrast, post-diagnostic use of simvastatin, a lipophilic statin, correlates with a decreased risk of breast cancer recurrence, providing a rationale for a prospective randomized clinical trial investigating simvastatin as an adjuvant therapy for breast cancer. Conclusion: As a whole, findings of pharmacoepidemiological studies based on DBCG data provide reassurance to physicians and healthcare personnel who provide supportive care during and after cancer (including prescriptions for comedications) and to breast cancer survivors for whom the risk of breast cancer recurrence is a major concern. [ABSTRACT FROM AUTHOR]

Aim: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. Material and methods: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. Results: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. Conclusion: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. [ABSTRACT FROM PUBLISHER]

Background: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors may improve outcomes in breast cancer patients. We investigated the association of aspirin, NSAIDs, and use of selective COX-2 inhibitors with breast cancer recurrence.Methods: We identified incident stage I-III Danish breast cancer patients in the Danish Breast Cancer Cooperative Group registry, who were diagnosed during 1996-2008. Prescriptions for aspirin (>99% low-dose aspirin), NSAIDs, and selective COX-2 inhibitors were ascertained from the National Prescription Registry. Follow-up began on the date of breast cancer primary surgery and continued until the first of recurrence, death, emigration, or 1 January 2013. We used Cox regression models to compute hazard ratios (HR) and corresponding 95% confidence intervals (95% CI) associating prescriptions with recurrence, adjusting for confounders.Results: We identified 34,188 breast cancer patients with 233,130 person-years of follow-up. Median follow-up was 7.1 years; 5,325 patients developed recurrent disease. Use of aspirin, NSAIDs, or selective COX-2 inhibitors was not associated with the rate of recurrence (HRadjusted aspirin = 1.0, 95% CI = 0.90, 1.1; NSAIDs = 0.99, 95% CI = 0.92, 1.1; selective COX-2 inhibitors = 1.1, 95% CI = 0.98, 1.2), relative to nonuse. Prediagnostic use of the exposure drugs was associated with reduced recurrence rates (HRaspirin = 0.92, 95% CI = 0.82, 1.0; HRNSAIDs = 0.86, 95% CI = 0.81, 0.91; HRsCOX-2inhibitors = 0.88, 95% CI = 0.83, 0.95).Conclusions: This prospective cohort study suggests that post diagnostic prescriptions for aspirin, NSAIDs, and selective COX-2 inhibitors have little or no association with the rate of breast cancer recurrence. Prediagnostic use of the drugs was, however, associated with a reduced rate of breast cancer recurrence. [ABSTRACT FROM AUTHOR]

Background: Opioids may alter immune function, thereby potentially affecting cancer recurrence. The authors investigated the association between postdiagnosis opioid use and breast cancer recurrence.Methods: Patients with incident, early stage breast cancer who were diagnosed during 1996 through 2008 in Denmark were identified from the Danish Breast Cancer Cooperative Group Registry. Opioid prescriptions were ascertained from the Danish National Prescription Registry. Follow-up began on the date of primary surgery for breast cancer and continued until breast cancer recurrence, death, emigration, 10 years, or July 31, 2013, whichever occurred first. Cox regression models were used to compute hazard ratios and 95% confidence intervals associating breast cancer recurrence with opioid prescription use overall and by opioid type and strength, immunosuppressive effect, chronic use (≥6 months of continuous exposure), and cumulative morphine-equivalent dose, adjusting for confounders.Results: In total, 34,188 patients were identified who, together, contributed 283,666 person-years of follow-up. There was no association between ever-use of opioids and breast cancer recurrence (crude hazard ratio, 0.98; 95% confidence interval, 0.90-1.1; adjusted hazard ratio, 1.0; 95% confidence interval, 0.92-1.1), regardless of opioid type, strength, chronicity of use, or cumulative dose. Breast cancer recurrence rates were lower among users of strongly (but not weakly) immunosuppressive opioids, possibly because of channeling bias among those with a high competing risk, because mortality was higher among users of this drug type.Conclusions: This large, prospective cohort study provided no clinically relevant evidence of an association between opioid prescriptions and breast cancer recurrence. The current findings are important to cancer survivorship, because opioids are frequently used to manage pain associated with comorbid conditions. [ABSTRACT FROM AUTHOR]

Purpose To describe long-term failure pattern after early-stage breast cancer in relation to local treatment (breast-conserving therapy (BCT) or mastectomy) and age. Materials and methods Cohort study with balanced 5-year age groups and prospectively collected data; 813 Danish lymph-node-negative breast cancer patients diagnosed in 1989–98 and treated with mastectomy ( N = 515) or BCT ( N = 298) and no adjuvant systemic treatment. Results The 20-year local recurrence (LR) risk was 20% after BCT; 8.7% after mastectomy. LR developed in mastectomy patients within the first 10 years; in BCT patients throughout the entire 20-year period. Younger patients’ (⩽45 years) 20-year LR risk was generally higher than older patients’ (>45 years) (19% vs. 5%, p < 0.001). In younger patients, LR was significantly associated with distant metastasis (DM) (hazard ratio (HR) = 2.7(1.8–4.2)) and 20-year breast-cancer mortality (HR = 2.7(1.7–4.4)). BCT was associated with higher 20-year breast-cancer mortality (HR = 1.5(1.0–2.4)) and higher 20-year all-cause mortality (HR = 1.7(1.2–2.5)) than mastectomy. In older patients, LR was not associated with DM, and breast-cancer mortality was similar for BCT and mastectomy. Conclusion BCT patients with no adjuvant systemic treatment developed LR throughout 20-year period and faced higher LR risk than mastectomy patients. LR was associated with DM among younger patients, and younger BCT patients had higher mortality than younger mastectomy patients. [ABSTRACT FROM AUTHOR]

Summary Much preclinical and epidemiological evidence supports the anticancer effects of statins. Epidemiological evidence does not suggest an association between statin use and reduced incidence of breast cancer, but does support a protective effect of statins—especially simvastatin—on breast cancer recurrence. Here, we argue that the existing evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins and we advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well tolerated, and inexpensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several trial design opportunities—including candidate predictive biomarkers of statin safety and efficacy—and offer solutions to the key challenges involved in the enrolment, follow-up, and analysis of such a trial. [ABSTRACT FROM AUTHOR]