Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review

Background

Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein thrombosis and pulmonary embolism in women <50 years given tamoxifen for breast cancer prevention.

Methods

We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20 mg per day) with placebo for five years in high-risk women <50 years. The absolute risk and relative risk (RR) for each outcome were estimated.

Results

The RR for endometrial cancer in women <50 years given tamoxifen is 1.19 (95% CI, 0.53–2.65; p = 0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23–4.31; p = 0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38–2.67; p = 0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55–2.43; p = 0.6).

Interpretation

The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50 years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention.     

CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen

Introduction

Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen.

Methods

This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis.

Results

In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups.

Conclusions

CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.     

What do we know and what don't we know about tamoxifen in the human uterus

Since its introduction in the early seventies, the list of indications for the use of the antiestrogen tamoxifen has been continuously expanded. Tamoxifen is now used for the treatment of metastatic breast cancer and for long-term and often indefinite administration as an adjuvant therapy. Large clinical trials in three countries are now evaluating the efficacy of tamoxifen as a preventive agent. However, tamoxifen therapy has been associated with an increased incidence of endometrial carcinoma. Laboratory and clinical data available to date on this controversial issue can be summarized as follows:

1. Tamoxifen can have an estrogenic effect on endometrium in the presence of low estrogen levels.
2. Tamoxifen treatment is probably associated with an increased incidence of endometrial cancer; however, this association appears to be linked to higher tamoxifen doses (40mg/d).
3. It is not known whether tamoxifen causes or allows the identification of occult endometrial carcinoma.
4. At the present time there is evidence for a tumor promoting effect of tamoxifen on endometrial cancer at a dose of 20 mg per day.
5. Replacement of tamoxifen by ‘pure’ antiestrogens or coadministration of progestins with tamoxifen do not appear to offer benefit unless clinical trials demonstrate a reduced incidence of endometrial problems.
6. Patientsmust be evaluated for pre-exsisting endometrical carcinoma before starting tamoxifen therapy.
7. Close followup of long-term tamoxifen patients with endometrial biopsies is recommended with individuals who experience symptoms.

     

Depressive symptoms are a risk factor for all-cause mortality: results from a prospective population-based study among 3,080 cancer survivors from the PROFILES registry

Background

The goal of this large prospective population-based study was to examine the association between depressive symptoms and all-cause mortality among cancer survivors up to 10 years post-diagnosis.

Methods

All currently alive individuals diagnosed with endometrial or colorectal cancer (CRC) between 1998 and 2007 or with lymphoma or multiple myeloma between 1999 and 2008, as registered in the Eindhoven Cancer Registry, received a questionnaire on depressive symptoms (Hospital Anxiety and Depression Scale (HADS)) in 2008 or 2009, respectively; 69 % (n?=?3,080) responded. Survival status was obtained from the Central Bureau for Genealogy.

Results

Clinically elevated levels of depressive symptoms (HADS cutoff value ≥8) were more prevalent in those who died compared to those who survived (38 vs. 19 %, respectively; p?<?0.0001). This was also evident across different types of cancer. After adjustment for independent predictors of all-cause mortality, 1–10-year survivors with depressive symptoms had an increased risk of death (hazard ratio (HR) 2.07; 95 % confidence interval (CI) 1.56–2.74; p?<?0.0001), and this was also found among 1–2-year survivors (HR, 2.20; 95 % CI, 1.41–3.43; p?<?0.001). Sub-analyses among CRC survivors gave the opportunity to adjust for metastasis and showed that depressive symptoms among 1–10-year CRC survivors and 1–2-year CRC survivors increased the risk of death (HR, 1.88; 95 % CI, 1.24–2.83; p?<?0.01 and HR, 2.55; 95 % CI, 1.44–4.51; p?<?0.001, respectively).

Conclusions

This study showed that patients with depressive symptoms had twofold risk for all-cause mortality, even after adjustment for major clinical predictors.

Implications for Cancer Survivors

Paying more attention to the recognition and treatment of depressive symptoms seems warranted since depressive symptoms are often underdiagnosed and undertreated in cancer patients.     

Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]

Introduction

Experimental and clinical data show that the oral bisphosphonate clodronate (Bonefos^®) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival.

Methods

1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated.

Results

Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event.

Conclusion

These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.     

Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer

Background

Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen.

Patients and methods

The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events.

Results

A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval ?3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated.

Conclusion

Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.     

Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification

Background

Breast cancer is a leading cause of morbidity and mortality in women worldwide. About 70 % of breast cancers are estrogen receptor (ER) positive. Blocking estrogen action by tamoxifen has been the treatment of choice in ER positive breast cancers for more than 30 years. In the past, several studies have revealed associations between gene copy number alterations and responsiveness to tamoxifen therapy, but so far no single gene copy number alteration could completely explain the response variation observed between individual breast cancer patients. Here, we set out to perform a simultaneous analysis of copy number alterations of several genes involved in the prognosis and response to therapy by multiplex ligation-dependent probe amplification (MLPA).

Methods

A case–control study was designed encompassing 170 non-metastatic ER positive breast cancer patients (case group?=?85, control group?=?85). All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced early recurrences while receiving tamoxifen treatment. 76 % of the patients of the case group and 73 % of the patients of the control group had received anthracycline-based adjuvant chemotherapy. Gene copy number alterations detected by MLPA in both groups were compared.

Results

Amplification of CCND1 (OR?=?3.13; 95 % CI?=?1.35 to 7.26; p?=?0.006) and TOP2A (OR?=?3.05; 95 % CI?=?1.13 to 8.24; p?=?0.022) were significantly more prevalent in the case group, compared to the control group. In a multivariate analysis CCND1 (p?=?0.01) and TOP2A (p?=?0.041) amplifications remained significant predictors of recurrence.

Conclusions

Our results indicate that CCND1 amplification may serve as a useful biomarker for hormone responsiveness, and that TOP2A amplification may serve as a useful prognostic biomarker.     

Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial

Background:

Tamoxifen has been associated with an increased risk of stroke. There is, however, little information on the effect in the post-treatment period. Using data from the Swedish Breast Cancer Group adjuvant trial of 5 vs 2 years of tamoxifen treatment, we now report both short-term and long-term effects on morbidity as well as mortality because of cerebrovascular disease.

Methods:

Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry was used to define events of disease. Hazard ratios (HRs) were estimated using Cox regression.

Results:

Comparing patients randomised to 5 years of tamoxifen with patients randomised to 2 years of tamoxifen, the incidence of cerebrovascular diseases was increased (HR 1.70, 95% CI 1.05–2.75) during the active treatment phase and reduced after the active treatment period (HR 0.78, 95% CI 0.63–0.96), and the difference in HR between the two time-periods was significant (P=0.0033). The mortality from cerebrovascular diseases was increased during the treatment period (HR 3.18, 95% CI 1.03–9.87) and decreased during the post-treatment period (HR 0.60, 95% CI 0.40–0.90) with a significant difference in HR between the two periods of follow-up (P=0.0066). Similar results were seen for subgroups of cerebrovascular diseases, such as stroke and ischaemic stroke.

Conclusion:

In an adjuvant setting, tamoxifen was associated with an increased risk of cerebrovascular disease during treatment, but a decreased risk in the post-treatment period.     

The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels

Purpose

Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the ¹³C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen.

Methods

In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype.

Results

CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5 % (R ² = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90 %, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB₅₀) values of 0.7–0.9) and genotype (CYP2D6 gene activity score of 1.0).

Conclusion

DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.     

Body mass index, tumor characteristics, and prognosis following diagnosis of early-stage breast cancer in a mammographically screened population

Purpose

Many studies suggest increased body mass index (BMI) is associated with worse breast cancer outcomes, but few account for variability in screening, access to treatment, and tumor differences. We examined the association between BMI and risk of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, and evaluated whether tumor characteristics differ by BMI among a mammographically screened population with access to treatment.

Methods

Using a retrospective cohort study design, we followed 485 women aged ≥40 years diagnosed with stage I/II breast cancer within 24 months of a screening mammogram occurring between 1988 and 1993 for 10-year outcomes. BMI before diagnosis was categorized as normal (<25 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²). Tumor marker expression was assessed via immunohistochemistry using tissue collected before adjuvant treatment. Medical records were abstracted to identify treatment, recurrence, and mortality. We used Cox proportional hazards to separately model the hazard ratios (HR) of our three outcomes by BMI while adjusting for age, stage, and tamoxifen use.

Results

Relative to normal-weight women, obese women experienced increased risk of recurrence (HR 2.43; 95 % CI 1.34–4.41) and breast cancer death (HR 2.41; 95 % CI 1.00–5.81) within 10 years of diagnosis. There was no association between BMI and all-cause mortality. Obese women had significantly faster growing tumors, as measured by Ki-67.

Conclusions

Our findings add to the growing evidence that obesity may contribute to poorer breast cancer outcomes, and also suggest that increased tumor proliferation among obese women is a pathway that explains part of their excess risk of adverse outcomes.     

Physical activity, additional breast cancer events, and mortality among early-stage breast cancer survivors: findings from the WHEL Study

Objective

Research suggests that physical activity is associated with improved breast cancer survival, yet no studies have examined the association between post-diagnosis changes in physical activity and breast cancer outcomes. The aim of this study was to determine whether baseline activity and 1-year change in activity are associated with breast cancer events or mortality.

Methods

A total of 2,361 post-treatment breast cancer survivors (Stage I?CIII) enrolled in a randomized controlled trial of dietary change completed physical activity measures at baseline and one year. Physical activity variables (total, moderate?Cvigorous, and adherence to guidelines) were calculated for each time point. Median follow-up was 7.1 years. Outcomes were invasive breast cancer events and all-cause mortality.

Results

Those who were most active at baseline had a 53% lower mortality risk compared to the least active women (HR = 0.47; 95% CI: 0.26, 0.84; p = .01). Adherence to activity guidelines was associated with a 35% lower mortality risk (HR = 0.65, 95% CI: 0.47, 0.91; p < .01). Neither baseline nor 1-year change in activity was associated with additional breast cancer events.

Conclusions

Higher baseline (post-treatment) physical activity was associated with improved survival. However, change in activity over the following year was not associated with outcomes. These data suggest that long-term physical activity levels are important for breast cancer prognosis.     

Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-α-negative breast cancer

Background:

Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation.

Purpose:

To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer.

Methods

Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point.

Results:

In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14–0.81; P=0.015), whereas the opposite was seen in the AR− group (HR=2.92; 95% CI=1.16–7.31; P=0.022). Interaction test was significant P<0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR=0.12; 95% CI=0.014–0.95 P=0.044), whereas patients with AR− tumours had worse outcome when treated with tamoxifen (HR=3.98; 95% CI=1.32–12.03; P=0.014). Interaction test was significant P=0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression.

Conclusions:

AR can predict tamoxifen treatment benefit in patients with ER− tumours and triple-negative breast cancer.     

Extraction of tamoxifen and its metabolites from formalin-fixed,paraffin-embedded tissues: an innovative quantitation method using liquid chromatography and tandem mass spectrometry

Purpose

Tamoxifen is a key therapeutic option for breast cancer treatment. Understanding its complex metabolism and pharmacokinetics is important for dose optimization. We examined the possibility of utilizing archival formalin-fixed paraffin-embedded (FFPE) tissue as an alternative sample source for quantification since well-annotated retrospective samples were always limited.

Methods

Six 15 μm sections of FFPE tissues were deparaffinized with xylene and purified using solid-phase extraction. Tamoxifen and its metabolites were separated and detected by liquid chromatography–tandem mass spectrometry using multiple-reaction monitoring.

Results

This method was linear between 0.4 and 200 ng/g for 4-hydroxy-tamoxifen and endoxifen, and 4–2,000 ng/g for tamoxifen and N-desmethyl-tamoxifen. Inter- and intra-assay precisions were <9 %, and mean accuracies ranged from 81 to 106 %. Extraction recoveries were between 83 and 88 %. The validated method was applied to FFPE tissues from two groups of patients, who received 20 mg/day of tamoxifen for >6 months, and were classified into breast tumor recurrence and non-recurrence. Our preliminary data show that levels of tamoxifen metabolites were significantly lower in patients with recurrent cancer, suggesting that inter-individual variability in tamoxifen metabolism might partly account for the development of cancer recurrence. Nevertheless, other causes such as non-compliance or stopping therapy of tamoxifen could possibly lead to the concentration differences.

Conclusions

The ability to successfully study tamoxifen metabolism in such tissue samples will rapidly increase our knowledge of how tamoxifen’s action, metabolism and tissue distribution contribute to breast cancer control. However, larger population studies are required to understand the underlying mechanism of tamoxifen metabolism for optimization of its treatment.     

High frequency microsatellite instability has a prognostic value in endometrial endometrioid adenocarcinoma, but only in FIGO stage 1 cases

Objectives

To analyze the prognostic value of microsatellite instability (MSI) in a population-based study of FIGO stage 1–4 endometrial endometrioid adenocarcinomas. Study Design: Survival analysis in 273 patients of MSI status and clinico-pathologic features. Using a highly sensitive pentaplex polymerase chain reaction to establish MSI status, cases were divided into microsatellite stable (MSS), MSI-low (MSI-L, 1 marker positive) and MSI-high (MSI-H, 2–5 markers positive).

Results

After 61 months median follow-up (1–209), 34 (12.5%) of the patients developed metastases but only 6.4% of the FIGO-1. MSI (especially as MSI-H versus MSS/MSI-Lcombined) was prognostic in FIGO-1 but not in FIGO2-4. The 5 and10 year recurrence-free survival rates were 98% and 95% in the MSS/MSI-L versus 85% and 73% in the MSI-H patients (P?=?0.005).

Conclusions

MSI-H status assessed by pentaplex polymerase chain reaction is an indicator of poor prognosis in FIGO 1, but not in FIGO 2–4 endometrial endometrioid adenocarcinomas.     

Cost-effectiveness of chemoprevention of breast cancer using tamoxifen in a postmenopausal US population

BACKGROUND:

Previous cost‐effectiveness analyses of tamoxifen therapy account for breast cancer risk reduction during active treatment but not for its persistent protective effect after active treatment.

METHODS:

A detailed, continuous time, mathematical model of breast cancer and healthcare processes was used to simulate a postmenopausal population aged <55 years in a virtual trial comparing tamoxifen treatment with no treatment for lifetime follow‐up. Unlike previous work, the current model of tamoxifen therapy is based on a meta‐analysis of 4 randomized, placebo‐controlled chemoprevention trials with breast cancer risk reduction continuing for 10 years after treatment termination. Cancer incidence and survival data were derived from Surveillance, Epidemiology and End Results statistics. Noncancer disease incidences, quality‐adjusted life year (QALY) utility weights, and costs were derived from the literature.

RESULTS:

Tamoxifen treatment (vs no treatment) saved 29 QALYs in a population of 1000 postmenopausal women aged <55 years with an additional cost of $333,000 over the population's lifetime (average cost‐effectiveness ratio, $11,530 per QALY). Tamoxifen therapy, compared with no treatment, was cost saving when higher risk populations were targeted (5‐year risk ≥1.66%). The cost‐effectiveness results were sensitive to parameters that characterized menopausal symptoms and adverse side effects of tamoxifen.

CONCLUSIONS:

The current results indicated that tamoxifen chemoprophylaxis for postmenopausal women aged <55 years is a cost‐effective health policy that reduces breast cancer incidence and improves life expectancy. Focusing on a postmenopausal population aged <55 years minimized the threat of adverse events associated with tamoxifen. Cancer 2011. © 2011 American Cancer Society.     

Association of prediagnostic physical activity with survival following breast cancer diagnosis: influence of TP53 mutation status

Purpose

Physical activity both before and after breast cancer diagnosis has been associated with improved survival. However, it is not clear whether this association differs by molecular features of the tumor or by recency of the physical activity to the time of diagnosis.

Methods

We examined the association of prediagnostic physical activity with survival in a cohort of 1,170 women with primary, incident, and histologically confirmed breast cancer, examining tumor molecular subtypes. Cox regression models were used to estimate hazard ratios (HR) and 95 % confidence intervals (95 % CI).

Results

Mean follow-up time was 87.4 months after breast cancer diagnosis; there were 170 deaths identified. Compared with inactive patients (<3 h/week), women with higher average lifetime physical activity (>6 h/week) had reduced risk of all-cause mortality (adjusted HR = 0.61, 95 % CI 0.40–0.95; p trend =0.04). There were no clear differences in the associations for lifetime and more recent physical activity. Lifetime physical activity was also weakly associated with decreased risk of breast cancer-specific mortality. Higher lifetime physical activity was associated with reduced risk of all-cause mortality among women with ER-positive tumors (HR = 0.52, 95 % CI 0.29–0.93) and mutant TP53 tumors (HR = 0.22, 95 % CI 0.06–0.72); however, no statistically significant interactions were observed for ER or TP53 status.

Conclusions

Our study further supports that prediagnostic physical activity improves overall survival following breast cancer and suggests that the associations of prediagnostic physical activity with survival following breast cancer may vary by molecular features of the tumor, particularly ER and TP53 status.     

The prognostic analysis of clinical breast cancer subtypes among patients with liver metastases from breast cancer

Background

To determine whether the inferior outcome noted with triple-negative breast cancer (TNBC) reflects a higher risk population among patients with breast cancer liver metastases.

Methods

A total of 123 patients with breast cancer liver metastases diagnosed at Tianjin Medical University Cancer Hospital were included in this study. Breast cancer subtype was assigned using immunohistochemistry or fluorescence in situ hybridization: hormone receptor (HR) positive (+)/human epidermal growth factor receptor 2 (HER2) negative (?), HR+/HER2+, HR?/HER2+ and triple-negative subtype. Clinical features and survival were evaluated in different subtypes.

Results

The median age at breast cancer diagnosis was 47 years (range, 23–67 years). Breast cancer subtype was confirmed in all patients (39.8% with HR+/HER2?, 24.4% with HR+/HER2+, 15.3% with HR?/HER2+ and 20.3% with TNBC). The median overall survival after liver metastases was 29 months (range, 4–89 months), and the overall 1-, 2- and 3-year survival rate was 68.3, 48.0 and 34.1%, respectively. Survival was found to be impacted by breast cancer subtype (P = 0.001), and was shortest for patients with TNBC. Time to liver metastases (TTLM) less than 24 months and liver metastasis lesions ≥3 were found to be important predictors of poor survival after liver metastases (P = 0.009 and 0.001, respectively).

Conclusions

The results indicate that clinical breast cancer subtype remains an independent prognostic predictor among patients with breast cancer liver metastases. Liver metastases arising from TNBC confers the worst prognosis, and novel agents capable of controlling intrahepatic and extrahepatic TNBC are needed.     

pHH3 and survivin are co-expressed in high-risk endometrial cancer and are prognostic relevant

Background:

Phosphohistone-H3 (pHH3) is a promising reliable mitotic count biomarker. Our purpose was to study the relationship between the novel proliferation marker pHH3 and the established anti-apoptotic marker survivin and consider their prognostic relevance in endometrial cancer.

Methods:

A total of 106 patients with endometrial cancer (type I/endometrioid, n=81; type II carcinomas, n=18) and simple hyperplasia without atypia (n=7) were investigated. pHH3 and survivin expression were assessed using immunohistochemistry from paraffin-embedded tissue blocks.

Results:

A strong positive correlation was observed between pHH3 and survivin expression (P<0.0001). Patients with high-grade tumours and patients with type II carcinomas expressed significantly more pHH3 and survivin than low grade and endometrioid tumours (P<0.0001, P<0.0001, P<0.0001, and P<0.0001, respectively). In univariate survival analysis, overexpression of pHH3 and survivin were associated with increased recurrence and mortality (P<0.0001, P<0.0001, P<0.0001, and P<0.0001, respectively), in the multivariable Cox regression analyses both pHH3 and survivin could be identified as independent parameters for overall survival (P=0.004, and P=0.023, respectively).

Conclusion:

In endometrial cancer, pHH3 and survivin were strongly positive correlated and were both associated with type II and high-grade tumours. Increasing expression levels of pHH3 and survivin were associated with adverse prognostic factors.     

Tamoxifen and the Rafoxifene analog LY117018: their effects on arachidonic acid release from cells in culture and on prostaglandin I<Subscript>2</Subscript>production by rat liver cells

Background  

Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention.     

Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients

To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2–115) months. Median age at diagnosis was 68 (range 36–91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient’s age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13–2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer.