Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4).

The 4th International Consensus Conference for Breast Cancer in Young Women (BCY4) took place in October 2018, in Lugano, Switzerland, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY3 with incorporation of new evidence to inform the guidelines. Areas of research priorities were also identified. This article summarizes the ESO-ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).

Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer.

Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% greater exemestane concentration (P<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index and had not received chemotherapy (all P<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (P<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.

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.

Predictors of recovery of ovarian function during aromatase inhibitor therapy.

BACKGROUND: Aromatase inhibitors (AIs) may cause a rise in estrogen levels due to ovarian function recovery in women with clinical chemotherapy-induced ovarian failure (CIOF). We carried out a prospective registry trial to identify predictors of ovarian function recovery during AI therapy. PATIENTS AND METHODS: Women with hormone receptor (HR)-positive breast cancer who remained amenorrheic and had hormonal levels consistent with ovarian failure after adjuvant chemotherapy were enrolled in a multi-institutional clinical trial of anastrozole. Subjects underwent frequent assessment using an ultrasensitive estradiol assay. Multivariable analysis was used to evaluate clinical and biochemical predictors of ovarian function recovery within 48 weeks. RESULTS: Recovery of ovarian function during AI therapy was observed in 13 of 45 (28.9%) assessable subjects after a median 2.1 months (range 0.6-11.9). Median age at chemotherapy initiation was statistically significantly different between those who regained ovarian function (43 years, range 40-51) and those who remained postmenopausal (49 years, range 44-52; P < 0.0001). CONCLUSIONS: A significant proportion of women with CIOF recover ovarian function during AI therapy, including a woman over age 50 at initiation of chemotherapy. Tamoxifen remains the standard of care for women with CIOF. If an AI is used, patients should be monitored frequently with high-quality estradiol assays. CLINICALTRIALS.GOV: NCT00555477.

Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo.

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1-3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

Modeling hot flushes and quality of life in breast cancer survivors.

OBJECTIVES: To evaluate the relationships among measures of hot flushes, perceived hot flush interference, sleep disturbance, and measures of quality of life while controlling for potential covariates (patient and treatment variables). METHODS: Breast cancer survivors (n = 395) due to receive aromatase inhibitor therapy provided demographic information, physiological hot flush data via sternal skin conductance monitoring, hot flush frequency via written diary and electronic event marker, hot flush severity and bother via written diary, and questionnaire data via the Hot Flash Related Daily Interference Scale, Pittsburgh Sleep Quality Index, the EuroQOL, Hospital Anxiety and Depression Scale and the Center for Epidemiologic Studies Depression Scale. RESULTS: Confirmatory factor analysis supported a two-factor model for hot flush symptoms (frequency and severity). Although there was strong convergence among self-reported hot flush measures, there was a high degree of unexplained variance associated with physiological measures. This suggests that self-report and physiological measures do not overlap substantially. The structural model showed that greater hot flush frequency and severity were directly related to greater perceived interference with daily life activities. Greater perceived interference, in turn, directly predicted greater sleep disruption, which predicted lower perceived health state and more symptoms of anxiety and depression. CONCLUSIONS: Findings suggest hot flush interference may be the most appropriate single measure to include in clinical trials of vasomotor symptom therapies. Measuring and ameliorating patients' perceptions of hot flush interference with life activities and subjective sleep quality may be the most direct routes to improving quality of life.

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.

Inflammatory cytokines and aromatase inhibitor-associated musculoskeletal syndrome: a case-control study.

BACKGROUND: The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers. METHODS: Patients with breast cancer were enrolled in a trial of adjuvant AI therapy. Changes in pain and function during therapy were assessed prospectively. We selected 30 cases with AIMSS and 22 controls without AIMSS, matched for demographics and prior therapy. Serum samples collected at baseline and during treatment were assayed for multiple inflammatory cytokines and lipid mediators using multiplex assays. RESULTS: Before AI therapy, mean serum concentrations of 6 of 36 assayed factors were statistically significantly lower in cases than controls (all P<0.003). No statistically significant changes during AI therapy relative to pre-treatment were observed between cases and controls for any of the inflammatory markers tested. CONCLUSION: AIMSS is probably not associated with a systemic inflammatory response. Pre-treatment cytokine levels may predict for development of AIMSS.

Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients.

The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen-receptor-positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n=297) were genotyped for CYP2D6 variants and assigned a 'score' based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months was tested. We observed a strong nonlinear correlation between higher CYP2D6 score and increased rates of discontinuation (r(2)=0.935, P=0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely.

Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer.

BACKGROUND: The purpose of this study was to provide practical, evidence-based guidelines for evaluating and treating common menopausal symptoms following breast cancer. METHODS: Literature review of the causes, assessment and management of menopausal symptoms in breast cancer patients. RESULTS: A number of nonhormonal treatments are effective in treating hot flashes. Whether pharmacological treatment is given will depend on the severity of symptoms and on patient wishes. For severe and frequent hot flashes, the best data support the use of venlafaxine, paroxetine and gabapentin in women with breast cancer. Side-effects are relatively common with all these agents. For vaginal dryness, topical estrogen treatment is the most effective but the safety of estrogens following breast cancer is not established. There are limited data on effective treatments for sexual dysfunction during menopause. CONCLUSION: Menopausal symptoms after breast cancer should be evaluated and managed as warranted using a systematic approach and may benefit from multidisciplinary input.

Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk.

Obesity is associated with increased risk of breast cancer in postmenopausal but not in premenopausal women. Many factors may be responsible for this difference. The aim of this study was to determine the mechanisms by which the genes related to the AMPK pathway, inflammation, and estrogen actions are affected by adiposity in breast tissue with the objective of identifying differences that may explain the different breast cancer risk in premenopausal and postmenopausal women. Random fine needle aspirates (rFNAs) of breast tissue were collected from 57 premenopausal and 55 postmenopausal women and were classified as normal weight, overweight, or obese. Expression levels of 21 target genes were determined using a TaqMan Low Density Array procedure. Breast tissue estradiol levels were measured by a liquid chromatography-tandem mass spectrometry procedure, and serum estradiol and follicle-stimulating hormone (FSH) were measured by a radioimmunoassay and an enzyme-linked immunosorbent assay, respectively. We found that in postmenopausal women, serum and tissue estradiol levels were increased in those who were overweight, and serum FSH levels were decreased in obese status. Interestingly, RPS6KB1, an AMPK downstream-responsive gene for protein synthesis and cell growth, and estrogen receptor α (encoded by the ESR1 gene) and its target gene GATA3 were significantly decreased in rFNA of premenopausal, obese women. In postmenopausal women, RPS6KB1, ESR1, and GATA3 expression remained unchanged in relation to adiposity. However, prostaglandin-endoperoxide synthase 2 (PTGS2), cyclin D1 (CCND1), and another ESR1 target gene, TFF1, were elevated in rFNA of obese postmenopausal women. Thus, as bodyweight increases, gene expression is indicative of increased proliferation in postmenopausal women but decreased proliferation in premenopausal women. Overall, our data reveal a novel process by which obesity promotes the risk of breast cancer in postmenopausal but not premenopausal women.

Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006.

Neoadjuvant (primary systemic) treatment has become a standard option for primary operable disease for patients who are candidates for adjuvant systemic chemotherapy, irrespective of the size of the tumor. Because of new treatments and new understandings of breast cancer, however, recommendations published in 2006 regarding neoadjuvant treatment for operable disease required updating. Therefore, a third international panel of representatives of a number of breast cancer clinical research groups was convened in September 2006 to update these recommendations. As part of this effort, data published to date were critically reviewed and indications for neoadjuvant treatment were newly defined.

New onset vasomotor symptoms but not musculoskeletal symptoms associate with clinical outcomes on extended adjuvant letrozole - Analyses from NCIC CTG MA.17.

PURPOSE: New onset symptoms on adjuvant aromatase inhibitors for hormone receptor positive early breast cancer may associate with clinical outcomes. We performed this exploratory analysis of the association of new onset musculoskeletal (MSK) and vasomotor (VM) symptoms with clinical outcomes in the NCIC CTG MA.17 trial 5 years of extended adjuvant endocrine therapy with letrozole after tamoxifen. METHODS: Symptoms were collected at baseline, 1, 6, and every 12 months on study. Multivariate Cox Models adjusting for age, nodal status, duration of tamoxifen and prior chemotherapy were used to compare disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) based on data collected before, and after, the unblinding between women with VM or MSK symptoms and those without. RESULTS: Data post-unblinding showed new VM symptoms on extended letrozole significantly improved DFS and DDFS when occurring 1 month (DFS HR 0.52, 95% CI, 0.28-0.96; p = 0.04; DDFS HR 0.49, 95% CI, 0.24-0.99; p = 0.046) and 6 months (DFS HR 0.43, 95% CI, 0.24-0.78; p = 0.006; DDFS HR 0.44, 95% CI, 0.22-0.85; p = 0.02) after treatment initiation. Those with new VM symptoms at 12 months also had a significantly better DFS (HR 0.47, 95% CI 0.26, 0.84; P = 0.01) and a trend in improved DDFS. Only a trend to improved OS was found for those with VM symptoms 6 month after treatment. No significant improvement was found for those with new MSK symptoms at any time point or for any endpoint. CONCLUSIONS: New onset VM symptoms with extended letrozole may be useful in predicting treatment benefit.

Does tamoxifen cause cancer in humans?

PURPOSE: To review the preclinical and clinical data on the carcinogenic potential of tamoxifen. DESIGN: A MEDLINE search on the carcinogenicity of tamoxifen was conducted and the literature reviewed. RESULTS: Because tamoxifen has estrogen-like effects on some tissues, such as the human uterus, there has been concern that tamoxifen could promote endometrial cancers in women on chronic tamoxifen therapy. Observations in some randomized trials of adjuvant tamoxifen therapy are consistent with a small, but real, increased risk of endometrial cancer in women who take tamoxifen. Since increased endometrial cancer incidence has not been observed in all studies of chronic tamoxifen therapy, there may be an element of detection bias. Laboratory studies have demonstrated that tamoxifen is hepatocarcinogenic in laboratory rats, but not in other species. This carcinogenicity in rats has been linked to the formation of DNA adducts. CONCLUSION: The incidence of endometrial cancer is increased in women who take tamoxifen. The data suggest that tamoxifen might be a tumor promoter in human endometrium. However, on the basis of the number of tumors seen by endometrial sampling of tamoxifen-treated women, the impact of tamoxifen as a tumor promoter is small. Women on chronic tamoxifen therapy should have routine annual gynecologic examinations and receive endometrial sampling only in the event of uterine bleeding. Unlike the data in rats, there is no conclusive evidence to link tamoxifen with an increased rate of hepatocellular cancer in humans; the contrasting carcinogenic potential may be attributed to substantial interspecies differences in the metabolism of tamoxifen.

When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer.

PURPOSE: c-erbB-2 (HER-2, c-neu) might play a role as a predictive factor in breast cancer. However, the clinical utility of the marker in this disease is still not established. We conducted a critical analysis of the literature, in which we reviewed the factors that contribute to the lack of acceptance of c-erbB-2 for clinical use and attempted to determine the predictive role of c-erbB-2 for response to specific therapies. METHODS: We conducted a MEDLINE literature search using the keywords c-erbB-2, HER2, neu, and breast cancer, reviewed the references included in each publication, and reviewed abstracts that have been reported in the 1997-2000 proceedings to the American Association of Cancer Research and American Society for Clinical Oncology annual meetings. RESULTS: The preclinical and clinical data reported to date suggest that amplification or overexpression of c-erbB-2 is a weak to moderate negative pure prognostic factor. c-erbB-2 seems to be a weak to moderate negative predictive factor for response to endocrine therapy. The marker is also a moderate negative predictive factor for response to alkylating agents and a moderate positive predictive factor for response to anthracyclines. The data regarding response to taxanes or radiotherapy are not sufficient to make recommendations regarding treatment decision making. Finally, c-erbB-2 is a strong predictive factor for response to trastuzumab. CONCLUSION: We conclude that, in the adjuvant setting, c-erbB-2 status should not be used to determine whether a woman should receive adjuvant systemic therapy (weak prognostic factor). In addition, c-erbB-2 status should not be used to determine whether a patient should receive endocrine therapy. When adjuvant chemotherapy is recommended, anthracycline-based therapy should be the preferred regimen for c-erbB-2-positive patients. However, when anthracyclines are contraindicated, alkylating agent-based therapy should not be withheld. To determine the true predictive role and strength of the marker for response to each therapy, prospective randomized clinical trials or formal meta-analyses are required.

New prognostic factors for breast cancer recurrence.

Decisions regarding the use of adjuvant therapy for breast cancer are strongly influenced by the risk of disease recurrence and death. These risks are now determined by examining the currently recognized breast cancer prognostic factors including clinical stage, axillary nodal status, tumor size and grade, hormone receptor status, and presence of lymphovascular involvement. Newer factors are being evaluated in an attempt to more precisely define disease-related prognosis. This article provides an overview of issues that need to be considered when analyzing studies of prognostic factors, as well as a review of the currently recognized and the newer candidate prognostic factors.

The Role of c-erbB-2 as a predictive factor in breast cancer.

Most women diagnosed with primary invasive breast cancer are potential candidates to receive adjuvant systemic treatment. Tumor markers that predict the likelihood of response to therapy might help select optimal treatment for individual patients. Of these, c-erbB-2 is the most promising marker. In the past 15 years, over 200 reports related to c-erbB-2 and breast cancer have been published. However, its clinical role remains unclear. c-erbB-2 might serve as either a pure prognostic factor, with no association with therapy, or as a predictive factor of benefit from specific types of systemic treatments. A recent overview suggested that c-erbB-2 is only a weak prognostic factor. A review of the literature suggests that c-erbB-2 overexpression might predict for relative, but not absolute, resistance to endocrine therapy in estrogen receptor-positive women. When adjuvant chemotherapy is indicated, c-erbB-2 positive patients may receive more benefit from anthracycline-containing regimens than alkylating agents. However, if anthracyclines are contraindicated, women with c-erbB-2 positive tumor do derive benefit from alkylating agents. Importantly, c-erbB-2 status appears critical for selecting patients who should receive trastuzumab. Well-designed prospective randomized clinical trials or formal meta-analysis will help to establish the predictive role of c-erbB-2.

A SNP in steroid receptor coactivator-1 disrupts a GSK3ß phosphorylation site and is associated with altered tamoxifen response in bone.

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.