Lapatinib plus Letrozole as First‐Line Therapy for HER‐2+ Hormone Receptor–Positive Metastatic Breast Cancer

Objective.

To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)⁺ human epidermal growth factor receptor (HER)-2⁺ tumors receiving first-line therapy for metastatic breast cancer (MBC).

Patients and Methods.

Postmenopausal women (n = 1,286) with HR⁺ MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2⁺ tumors. The primary endpoint was progression-free survival (PFS) in HER-2⁺ patients.

Results.

Results in the HR⁺ HER-2⁺ population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53–0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2.

Conclusions.

The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2.     

Lipid concentrations in postmenopausal women on letrozole after 5?years of tamoxifen: an NCIC CTG MA.17 sub-study

To evaluate changes in serum lipid parameters (cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]), in postmenopausal women receiving letrozole after tamoxifen therapy. MA.17L is a sub-study of MA.17, a double-blind, placebo-controlled trial of extended adjuvant letrozole. Eligible postmenopausal women were non-hyperlipidemic and not on lipid-lowering drugs. This analysis considers the 183 patients on the letrozole arm. Lipid parameters evaluated at baseline, 6?months, 12?months, and yearly thereafter until completion of 5?years of letrozole. The median duration of letrozole treatment was 5.0?years with a range from 0.03 to 6.05?years. After 5?year tamoxifen, patients on letrozole experienced significant increases from baseline in total cholesterol, LDL cholesterol, and Lp(a) at all study time points but no statistically significant changes in triglycerides. Specifically, a statistically significant increase was found at 60?months in total cholesterol [mean percentage change from baseline (PC) 5.27; p?=?0.003], HDL cholesterol (mean PC 6.75; p?=?0.003), LDL cholesterol (mean PC 10.02; p?=?0.001), Lp(a) (mean PC 105.95; p?<?0.0001). 103 (56?%) women in the study had clinically significantly elevated levels of Lp(a) (106?% above baseline) after 5?years of therapy. The results were similar after excluding the 21?% of patients who had ever received anti-lipid treatment. Significant increases in total cholesterol, HDL cholesterol, LDL cholesterol, and, most notably, Lp(a) in postmenopausal women were observed following 5?years of adjuvant letrozole treatment and after 5?years of tamoxifen therapy and such patients should have monitoring of their lipid levels in clinical practice.     

Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

Background:

Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment.

Methods:

Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis.

Results:

Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues.

Conclusion:

These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.     

Quality of Life in Hormone Receptor–Positive HER‐2+ Metastatic Breast Cancer Patients During Treatment with Letrozole Alone or in Combination with Lapatinib

Background.

A phase III trial compared lapatinib plus letrozole (L + Let) with letrozole plus placebo (Let) as first-line therapy for hormone receptor (HR)⁺ metastatic breast cancer (MBC) patients. The primary endpoint of progression-free survival (PFS) in patients whose tumors were human epidermal growth factor receptor (HER)-2⁺ was significantly longer for L + Let than for Let (8.2 months versus 3 months; p = .019). This analysis focuses on quality of life (QOL) in the HER-2⁺ population.

Methods.

QOL was assessed at screening, every 12 weeks, and at withdrawal using the Functional Assessment of Cancer Therapy–Breast (FACT–B). Changes from baseline were analyzed and the proportions of patients achieving minimally important differences in QOL scores were compared. Additional exploratory analyses evaluated how QOL changes reflected tumor progression status.

Results.

Among the 1,286 patients randomized, 219 had HER-2⁺ tumors. Baseline QOL scores were comparable in the two arms. Mean changes in QOL scores were generally stable over time for patients who stayed on study. The average change from baseline on the FACT-B total score in both arms was positive at all scheduled visits through week 48. There was no significant difference between the two treatment arms in the percentage of QOL responders.

Conclusion.

The addition of lapatinib to letrozole led to a significantly longer PFS interval while maintaining QOL during treatment, when compared with letrozole alone, thus confirming the clinical benefit of the combination therapy in the HR⁺ HER-2⁺ MBC patient population. This all oral regimen provides an effective option in this patient population, delaying the need for chemotherapy and its accompanying side effects.     

A Pilot Study of Estradiol Followed by Exemestane for Reversing Endocrine Resistance in Postmenopausal Women With Hormone Receptor‐Positive Metastatic Breast Cancer

Background.

Endocrine resistance is a frequent complication, and strategies to reverse it are a high research priority for metastatic breast cancer (MBC) that is hormone receptor positive. Preclinical data suggest re-exposure to estrogen induces tumor regression in tamoxifen-resistant tumors. We conducted a pilot study to determine whether short-term estradiol exposure would reverse endocrine resistance and resensitize tumors

Methods.

Postmenopausal women with estrogen receptor-positive MBC whose disease had progressed after receiving at least one prior endocrine therapy were eligible for the study. Patients were initially treated with 6 mg/day estradiol, and those who had not progressed after 3 months were then switched to exemestane.

Results.

Thirteen patients were evaluable for toxicity and response. No grade 3 or 4 toxicities were observed. Of the 13 patients who initiated estradiol therapy, 6 patients (46%) had not experienced disease progression at month 3 and were switched to exemestane. On exemestane, disease progression was documented in five patients, with one having stable disease as best response. Median progression-free survival for all patients was 4.8 months (range: 0.6–9.5 months).

Conclusion.

Treatment with an estrogen prior to resuming antiestrogen treatments was not effective at reversing hormone resistance; however, low-dose estradiol treatment had measurable clinical activity with minimal toxicity and should be considered as a therapeutic option for hormone-refractory MBC.     

Lack of association between oestrogen receptor polymorphisms and change in bone mineral density with tamoxifen therapy

Background:

Tamoxifen, a selective oestrogen receptor (ER) modulator, increases bone mineral density (BMD) in postmenopausal women and decreases BMD in premenopausal women. We hypothesised that inherited variants in candidate genes involved in oestrogen signalling and tamoxifen metabolism might be associated with tamoxifen effects in bone.

Methods:

A total of 297 women who were initiating tamoxifen therapy were enrolled in a prospective multicentre clinical trial. Lumbar spine and total hip BMD values were measured using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of tamoxifen therapy. Single-nucleotide polymorphisms (SNPs) in ESR1, ESR2, and CYP2D6 were tested for associations in the context of menopausal status and previous chemotherapy, with a mean percentage change in BMD over 12 months.

Results:

The percentage increase in BMD was greater in postmenopausal women and in those patients who had been treated with chemotherapy. No significant associations between tested SNPs and either baseline BMD or change in BMD with 1 year of tamoxifen therapy were detected.

Conclusion:

The evaluated SNPs in ESR and CYP2D6 do not seem to influence BMD in tamoxifen-treated subjects.     

Subjective cognitive complaints one year after ceasing adjuvant endocrine treatment for early-stage breast cancer

Background:

In the BIG 1-98 trial objective cognitive function improved in postmenopausal women 1 year after cessation of adjuvant endocrine therapy for breast cancer. This report evaluates changes in subjective cognitive function (SCF).

Methods:

One hundred postmenopausal women, randomised to receive 5 years of adjuvant tamoxifen, letrozole, or a sequence of the two, completed self-reported measures on SCF, psychological distress, fatigue, and quality of life during the fifth year of trial treatment (year 5) and 1 year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. Subjective cognitive function and its correlates were explored.

Results:

Subjective cognitive function and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement for hot flushes (P=0.0005). No difference in changes was found between women taking tamoxifen or letrozole. Subjective cognitive function was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman''s R=0.80). Correlations between SCF and the other patient-reported outcomes were generally low.

Conclusion:

Improved objective cognitive function but not SCF occur following cessation of adjuvant endocrine therapy in the BIG 1-98 trial. The substantial correlation of SCF scores over time may represent a stable attribute.     

Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: a phase I/II study

Purpose.

Controversy exists about whether vaginal estrogens interfere with the efficacy of aromatase inhibitors (AIs) in breast cancer patients. With the greater incidence of vaginal atrophy in patients on AIs, a safe and effective nonestrogen therapy is necessary. We hypothesized that vaginal testosterone cream could safely treat vaginal atrophy in women on AIs.

Methods.

Twenty-one postmenopausal breast cancer patients on AIs with symptoms of vaginal atrophy were treated with testosterone cream applied to the vaginal epithelium daily for 28 days. Ten women received a dose of 300 μg, 10 received 150 μg, and one was not evaluable. Estradiol levels, testosterone levels, symptoms of vaginal atrophy, and gynecologic examinations with pH and vaginal cytology were compared before and after therapy.

Results.

Estradiol levels remained suppressed after treatment to <8 pg/mL. Mean total symptom scores improved from 2.0 to 0.7 after treatment (p < .001) and remained improved 1 month thereafter (p = .003). Dyspareunia (p = .0014) and vaginal dryness (p <.001) improved. The median vaginal pH decreased from 5.5 to 5.0 (p = .028). The median maturation index rose from 20% to 40% (p < .001). Although improvement in total symptom score was similar for both doses (−1.3 for 300 μg, −0.8 for 150 μg; p = .37), only the 300-μg dose was associated with improved pH and maturation values.

Conclusions.

A 4-week course of vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels. Longer-term trials are warranted.     

High-Dose Toremifene for Fulvestrant-Resistant Metastatic Breast Cancer: A Report of Two Cases

Introduction

Hormone receptor (HR)-positive metastatic breast cancer (MBC) is usually treated with hormone therapy. In postmenopausal females, aromatase inhibitors (AIs) are usually used as first-line therapy, and fulvestrant is used subsequently. The optimal treatment beyond fulvestrant has not been established. We experienced two cases in which high-dose toremifene (hdTOR) was effective after the failure of AIs and fulvestrant.

Case 1

A 73-year-old female with HR-positive left breast cancer (T2N1M0) underwent preoperative chemotherapy and mastectomy with axillary dissection. Computed tomography (CT) revealed liver tumors in S7 (23 mm) and S8 (25 mm) during adjuvant letrozole therapy, so fulvestrant was started. The tumors initially decreased in size (23 and 22 mm), but then progressed (36 and 25 mm). Treatment was changed to hdTOR, and the tumors shrunk to 26 mm (S7) and 24 mm (S8), and she was stable for 6 months while receiving hdTOR.

Case 2

An 81-year-old female with HR-positive left breast cancer (T2N1M0) underwent left mastectomy and axillary dissection. CT revealed liver tumors in S7 (20 mm) and S8 (11 mm) during adjuvant letrozole therapy, so fulvestrant treatment was started. The tumor in S7 shrunk (13 mm), but the tumor in S8 slightly progressed (13 mm), and both tumors progressed (14 and 18 mm) after 6 months. Treatment was changed to hdTOR, and the tumors slightly shrunk (12 and 14 mm) after 6 months. hdTOR has been continued for 9 months.

Conclusion

hdTOR was effective for MBC after multiple hormone therapies, likely because it acts via a different mechanism of action.Key words: Secondary breast neoplasm, Hormone therapy, High-dose toremifene     

Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction

Background:

Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed.

Methods:

Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter.

Results:

We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone.

Conclusion:

Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post-menopausal women who require treatment with letrozole, ZA should also be considered.     

Survival Benefit of Zoledronic Acid in Postmenopausal Breast Cancer Patients Receiving Aromatase Inhibitors

Purpose

A growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors.

Methods

Between January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines.

Results

The baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99).

Conclusion

Our findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.     

Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation

Background:

The Intergroup Exemestane Study (IES) (ISRCTN11883920) demonstrated improved survival for postmenopausal women with ER-positive/unknown primary breast cancer who switched to exemestane after 2–3 years tamoxifen, compared with those continuing on tamoxifen to complete 5 years therapy. This was achieved without detriment to on-treatment quality-of-life (QoL). We report on- and post-treatment QoL impact in IES.

Methods:

A total of 582 patients from 8 countries participated in the QoL substudy. Functional Assessment of Cancer Therapy–Breast (FACT-B) and endocrine symptom subscale (ES) were completed at baseline, 3, 6, 9, 12, 18, 24, 30, 36, 48 and 60 months. The primary endpoint was FACT-B Trial Outcome Index (TOI); secondary endpoints included severity of individual endocrine symptoms.

Results:

Both the groups showed gradual improvement in overall QoL and lessening of total endocrine symptoms post treatment compared with baseline (P<0.002). There was no evidence of any between-group differences in TOI. Vasomotor complaints remained high on treatment. Vaginal discharge was more frequent (P<0.01) with tamoxifen up to 24 months from baseline. In both the groups, post-treatment libido did not recover to baseline levels.

Conclusion:

Clinical benefits of switching to exemestane are accompanied by good overall QoL. Although some symptoms persist, the majority of endocrine symptoms improve after treatment completion.     

Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration

Background.

Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival.

Methods.

The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study.

Results.

On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045–2.006; p < .03) in zoledronic acid–treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65–1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87–2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome.

Conclusions.

Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.     

Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects

Background:

Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy.

Methods:

Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment.

Results:

Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed.

Conclusion:

Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.     

Bosutinib in Combination With the Aromatase Inhibitor Letrozole: A Phase II Trial in Postmenopausal Women Evaluating First‐Line Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor‐Positive/HER2‐Negative Breast Cancer

Background.

Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2− BC.

Methods.

Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy.

Results.

Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy’s law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2.

Conclusion.

The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.     

Relationship of serum estrogens and estrogen metabolites to postmenopausal breast cancer risk: a nested case-control study

Introduction

Elevated levels of circulating estrogens are linked to breast cancer risk among postmenopausal women but little is known about the importance of estrogen metabolism. A recently developed liquid chromatography tandem mass spectrometry-based method (LC-MS/MS) measuring a panel of 15 estrogen metabolites (EM) has been evaluated in one study, linking high levels of 2-pathway metabolites relative to the parent estrogens to reduced breast cancer risk. We analyzed this panel of EM in a nested case-control study of postmenopausal breast cancer.

Methods

Between 1977 and 1987, 6,915 women provided blood samples to the Columbia Missouri Serum Bank and were followed for incident breast cancer through December 2002. We studied 215 postmenopausal breast cancer cases and 215 matched controls who were postmenopausal and not using exogenous hormones at the time of blood draw. EM were examined individually, grouped by pathway (hydroxylation at the C-2, C-4 or C-16 positions of the steroid ring) and by ratios of the groupings. Logistic regression models controlling for matching and breast cancer risk factors were used to calculate quartile-specific odds ratios (ORs) and 95% CIs.

Results

Significant elevated risks were not observed for individual EM, except for quartiles of 16-epiestriol (P trend = 0.07). The OR for total EM, the parent estrogens estrone and estradiol, and 2-pathway catechol EM (2-hydroxyestrone and 2-hydroxyestradiol) were elevated but the trends were not statistically significant. Among 2-pathway metabolites, risks for the highest levels of 2-hydroxyestrone-3-methyl ether and 2-methoxyestradiol were reduced; ORs for women in the highest versus lowest quartiles were 0.57 (95% CI = 0.33 to 0.99) and 0.53 (95% CI = 0.30 to 0.96), respectively. Overall, women with higher levels of 2-pathway EM had a reduced risk of breast cancer, which remained after accounting for levels of parent EM, 4-pathway EM and 16-pathway EM (all trends, P <0.11).

Conclusions

Women with more extensive hydroxylation along the 2-pathway may have a reduced risk of postmenopausal breast cancer. Further studies are needed to clarify the risks for specific EM and complex patterns of estrogen metabolism. This will require aggregation of EM results from several studies.     

Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses' Health Study II

Introduction

Prior research supports an association between endogenous sex steroids and breast cancer among postmenopausal women; the association is less clear among premenopausal women.

Methods

We evaluated the associations between estrogens, androgens, progesterone and sex hormone binding globulin (SHBG) and breast cancer in a nested case-control study in the Nurses'' Health Study II. Between 1996 and 1999, 29,611 participants provided blood samples; 18,521 provided samples timed in early follicular and mid-luteal phases of the menstrual cycle. A total of 634 women, premenopausal at blood collection, developed breast cancer between 1999 and 2009 and were matched to 1,264 controls (514 cases and 1,030 controls with timed samples). We used conditional logistic regression controlling for breast cancer risk factors for overall analyses; unconditional logistic regression additionally controlling for matching factors was used for subgroup analyses.

Results

In analyses of premenopausal estrogens including breast cancers diagnosed both before and after menopause, there was no association between follicular estradiol, estrone and free estradiol and risk of either total or invasive breast cancer. Luteal estradiol was positively associated with estrogen receptor positive (ER+)/progesterone receptor positive (PR+) cancers (5^th vs. 1^st quintile odds ratio (OR): 1.7 (95% confidence interval (CI): 1.0 to 2.9), P_trend = 0.02). Luteal estrone, free estradiol and progesterone were not associated with risk. Androgens were suggestively or significantly associated with risk when the sample was restricted to invasive tumors (for example, testosterone: OR: 1.4 (1.0 to 2.0), P_trend = 0.23) and ER+/PR+ disease (testosterone: OR: 1.7 (1.1 to 2.6) P_trend = 0.10; dehydroepiandrosterone sulfate (DHEAS) OR: 1.3 (0.8 to 2.0) P_trend = 0.05). SHBG was not associated with breast cancer risk. The results varied by menopausal status at diagnosis, with follicular estradiol suggestively positively associated with breast cancers in women premenopausal at diagnosis (OR: 1.1 (0.9 to 1.3) and significantly inversely associated with postmenopausal disease (OR: 0.6 (0.4 to 0.9); P_{heterogeneity} < 0.01).

Conclusions

Androgens were associated with modestly increased risk of breast cancer in this population, with stronger associations for invasive and ER+/PR+ disease. Luteal phase estradiol levels were suggestively associated with ER+/PR+ tumors but no other strong associations were observed with estrogens. Associations with follicular phase estrogens may vary by menopausal status at diagnosis, but case numbers were limited. Additional studies to confirm the role of premenopausal hormones in the etiology of both premenopausal and postmenopausal breast cancer are needed.     

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole

Background:

Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer.

Methods:

Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman''s rho) between the ES levels and BMI were assessed.

Results:

Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0–67.2, n=150) when BMI was <25.0 kg m⁻²; 65.6 (57.8–74.6, n=154) when 25.0–29.9 kg m⁻²; 59.3 (47.1–74.6, n=50) when 30.0–34.9 kg m⁻²; and 43.3 (23.0–81.7, n=16) when ⩾35.0 kg m⁻². No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed.

Conclusions:

Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.     

Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer

Background:

Body mass index (BMI) has an impact on survival outcome in patients treated with aromatase inhibitors (AIs). Obesity is associated with an increased body aromatisation and may be a cause of insufficient estradiol depletion.

Methods:

Sixty-eight postmenopausal oestrogen receptor-positive patients with early breast cancer were prospectively included in this study. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were analysed immediately in the clinical routine lab and in a dedicated central lab before (T1) and 3 months after start with aromatase inhibitors (T2).

Results:

A total of 40 patients were normal or overweight (non-obese: BMI 18.5–29.9 kg m⁻²) and 28 were obese (BMI⩾30 kg m⁻²). Aromatase inhibitors significantly suppressed estradiol serum levels (T1: 19.5 pg ml⁻¹, T2: 10.5 pg ml⁻¹, P<0.01) and increased FSH serum levels (T1: 70.2 mIU ml⁻¹, T2: 75.7 mIU ml⁻¹, P<0.05). However, after 3 months of AI treatment, estradiol levels of obese patients were nonsignificantly higher compared with non-obese patients (12.5 pg ml⁻¹ vs 9.0 pg ml⁻¹, P=0.1). This difference was reflected by significantly lower FSH serum levels in obese compared with non-obese patients (65.5 mIU ml⁻¹ vs 84.6 mIU ml⁻¹, P<0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine as well as in the dedicated central lab.

Conclusion:

Aromatase inhibitors are less efficient at suppressing estradiol serum levels in obese when compared with non-obese women.     

Prolactin serum levels and breast cancer: relationships with risk factors and tumour characteristics among pre- and postmenopausal women in a population-based case–control study from Poland

Background:

Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case–control study conducted in two cities in Poland (2000–2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases.

Methods:

We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression.

Results:

Prolactin levels were associated with nulliparity in premenopausal (P=0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P=0.0008) and direct association with use of recent/current hormone therapy (P=0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P=0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status.

Conclusions:

Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations.