Aromatase Inhibitors In Patients Research Articles

Pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, HER2-positive metastatic breast cancer: A randomized phase II study (PERTAIN).

TPS654^ Background: Resistance to endocrine therapy in patients (pts) with breast cancer remains a major clinical concern. Preclinical studies suggest that complete blockade of the hormone receptor (HR) combined with the inhibition of HER family members may be necessary to overcome resistance and improve clinical outcome in HR-positive and HER2-positive breast cancer (BC). The combination of pertuzumab (P) and trastuzumab (H) with docetaxel significantly improves patient outcome by blocking, more efficiently and completely, the HER signalling pathway. This benefit, however, may be smaller in HR-positive patients. PERTAIN is the first clinical trial to study whether a more potent blockade of the HER pathway with P and H in combination with endocrine therapy may restore or enhance endocrine sensitivity of HER2-positive BC and provide an effective treatment option in pts with HER2-positive and HR-positive MBC. Methods: PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal women with HER2- and HR-positive BC, studying the efficacy of the combination of P plus H with an aromatase inhibitor (AI) as first-line therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm 1). Pts in either arm may also receive induction chemotherapy (docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion. Study medication will be administered until disease progression or unacceptable toxicity. Pts must not have previously been treated with anti-HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and must have no CNS involvement or clinically significant cardiovascular disease. The primary endpoint is PFS, and secondary endpoints include overall survival, overall response rate, clinical benefit rate, duration of response, time to response, safety and tolerability, and quality of life. The study opened in January 2012 and will recruit 250 pts. Analysis of the primary endpoint will be performed after 165 PFS events using the Kaplan-Meier approach.

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Digoxin, a phyto-estrogen, binds with estrogen receptors (ER) and can cause gynecomastia. Among women currently using digoxin, breast and uterus cancer incidences are significantly increased (approximate risk ratios, 1.3-1.5). Both cancers are often estrogen sensitive. In contrast, ovary and cervix cancers are relatively estrogen insensitive, and incidence is unaffected by digoxin exposure. When digoxin use stops, incidence rapidly reverts to that in nonusers. These patterns parallel those of estrogen, suggesting that digoxin works via ER-stimulated proliferation of ductal and/or acinar cells, accelerating the growth of nascent cancers. Also consistent with an estrogenic effect, men using digoxin have a small but significant reduction in prostate cancer (risk ratio, 0.76). Other estrogen-like drugs, particularly spironolactone, should be investigated for similar effects. The effect of digoxin use in women being treated for breast cancer or in survivors is unknown. Women with estrogen-sensitive cancers on adjuvant therapy may take tamoxifen, which blocks ERs. However, postmenopausal patients may use aromatase inhibitors, which block estrogen production while leaving ERs susceptible to digoxin. If adverse effects are found, tamoxifen may be preferred over aromatase inhibitors in patients receiving estrogen-mimicking drugs. Alternatively, other cardiotropic drugs might be considered in women with or at high risk of developing estrogen-sensitive cancers.

Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients

BackgroundIn breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or ‘flare’ response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response.MethodsPatients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis.ResultsForty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%.ConclusionsSubstantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.

Putting the Cardiovascular Safety of Aromatase Inhibitors in Patients with Early Breast Cancer into Perspective

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.

MEDI-573 as a novel approach to IGF-1R and IR-A signaling inhibition by blocking IGF ligands: Phase I PK/PD, safety data, and disease linkage studies in breast cancer.

271 Background: MEDI-573 is a dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin receptor-A (IR-A) signaling pathways, which play a role in breast and other epithelial cancers. By sparing IR-B and its hybrid receptors, MEDI-573 is expected to achieve antitumor activity without perturbing glucose homeostasis. Methods: In a 3 + 3 dose-escalation trial ( NCT00816361 ), patients with advanced solid tumors, KPS ≥ 60, received MEDI-573 as a weekly 1-hr IV infusion at 0.5, 1.5, 5, 10, or 15 mg/kg every 21 days. Objectives included determination of MTD, safety profile, pharmacokinetics (PK), pharmacodynamics, and tumor response. In a separate biomarker study, mRNA expression of IR-A and IR-B was compared in HR+/HER- breast cancers. Results: Patients included 13M/12F (17 evaluable for efficacy at data cutoff); median age 59 yrs (range 37-78). No DLTs, drug-related SAEs, or significant toxicity patterns were reported. Forty-five AEs were considered treatment-related (% of patients): decreased appetite (28%), fatigue (24%), nausea (20%), diarrhea (16%), and anemia (12%). Hyperglycemia occurred in 2 patients, 1 with evidence of prestudy insulin resistance. No other significant changes in plasma glucose levels occurred. MEDI-573 had dose-proportionality, with AUC of 415 ± 165, 597 ± 298, and 1940 ± 904 d*μg/mL at 5, 10, and 15 mg/kg, respectively. Suppression of free IGF-1 and -2 was fully achieved at doses ≥ 5 mg/kg. Stable disease spanning ≥ 12 wks (range 12-36+) was seen in 6/17 patients. No antidrug antibodies were reported. In a study to identify breast cancer subsets that are dependent on IGF signaling, the IR-A:IR-B ratio was significantly higher in HR+/HER2- breast cancer than matched adjacent normal tissues and in proliferative luminal B than in luminal A breast cancer. Conclusions: MEDI-573 showed acceptable safety and favorable PK profiles without significant changes in glucose levels. The IR-A:IR-B ratio supports a biomarker approach for MEDI-573 patient stratification. A biomarker-rich phase Ib/II study of MEDI-573 with an aromatase inhibitor in patients with advanced HR+/HER2- breast cancer opens in 2011.

ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.

Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER(+) xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.

Drug safety evaluation of exemestane

Introduction: Hormone-dependent breast cancer can be successfully treated by either blocking the estrogen receptor, as with tamoxifen, or reducing the production of estrogens, as with aromatase inhibitors. Exemestane is a third-generation aromatase inhibitor used in the treatment of estrogen-receptor-positive breast cancer in postmenopausal women. In various trials, exemestane has shown superiority over tamoxifen in both efficacy and safety. Furthermore, aromatase inhibitors are gaining territory in the metastatic, as well as the early, setting for treating patients with breast cancer.Areas covered: The authors describe the mechanism of action and pharmacokinetic/pharmacodynamic characteristics of exemestane and discuss its efficacy and safety within the framework of currently approved and potential new indications. The reader can expect a full update on the characteristics of exemestane, including its efficacy and safety profile compared with tamoxifen and other third-generation aromatase inhibitors.Expert opinion: Exemestane is a safe drug due to its steroidal structure, which blocks aromatase at a different site to nonsteroidal AIs (eg., anastrozole and letrozole). Noncross-resistance with nonsteroidal aromatase inhibitors makes it an attractive alternative for all clinical indications of aromatase inhibitors in patients with breast cancer.

Abstract P5-11-16: Cognitive Effects of Endocrine Therapy in Patients with Breast Cancer

Abstract Background: Adjuvant endocrine therapy is the mainstay in the therapy of primary breast cancer. However, the impact of endocrine therapy on cognitive function in patients with breast cancer is still unclear. Numerous studies suggest a protective effect of estrogens on neurons. From these findings it has been derived that the almost complete estrogen deprivation by aromatase suppression would modify cognitive performances. The primary aim of our study was to ascertain, whether neurocognitive functioning is altered in breast cancer patients receiving various endocrine therapies. Patients and Methods: In a cross sectional study we investigated 80 post-menopausal women with breast cancer. Memory, spatial cognition, processing speed and attention were evaluated. Patients who ever received chemotherapy were not included. To compare cognitive task performance we constituted four treatment groups (see tab. 1). Tab. 1 Groups and Medication Patient characteristics were equally distributed, however, “switch” patients had received significantly more hormone replacement therapy before the onset of breast cancer than all other groups. We also evaluated mood, depression, anxiety, pre-morbid intelligence and self-perception of memory in order to receive homogenous groups. All participants were interviewed about their compliance to their medication. In this study, we used univariate statistical analyses of variance (ANOVA) and we calculated the effect-sizes of significant values. In case of lacking normal distribution we applied non-parametric statistics. Results: Women who solely received aromatase inhibitor treatment showed a significant impairment of general memory (p=0.01, d=1.15) and verbal memory (p=0.026, d=0.97) in comparison to the control group. In more than 50% of the aromatase inhibitor patients we found below-average performance concerning verbal memory compared to normative data. The aromatase inhibitor group performed significantly worse than the tamoxifen-(p=0.035, d=0.64) and the “switch-group” (p=0.03, d=0.91) with regard to attention. With respect to their spatial abilities, no significant differences in navigation and in mental rotation were noted. With regard to path integration we solely ascertained significant lower results of the aromatase inhibitor patients compared with the tamoxifen group (p=0.04). Overall, no differences were observed between the “switch”- and the tamoxifen patients. Surprisingly, most patients perceived their own memory performance as averaged. Self-perception of memory correlated with anxiety and depression but not with test scores. Conclusion: Treatment with tamoxifen alone seems to be less harmful for cognitive abilities than treatment with aromatase inhibitors alone. Patient may benefit from prior tamoxifen therapy when sequentially treated with aromatase inhibitors however this observation must be confirmed in further studies as well as the potential role of prior hormone replacement therapy and the objective adherence to therapy assessed by serum drug levels measurements. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-16.

Patient Characteristics and Patterns of Therapy Use among Patients Newly Diagnosed with Early Breast Cancer: Results from a US Claims Data Analysis.

Abstract Background: Following a diagnosis of early breast cancer (BC), there are a variety of treatment options open to physicians. However, with the development of alternative therapies and rapidly changing clinical guidelines, there are limited data available evaluating current patterns of care. This study investigated current treatment patterns following an initial diagnosis of early BC and examined demographic and clinical differences among patients receiving tamoxifen versus aromatase inhibitors (AI) as a preliminary analysis to inform a more in-depth study assessing early BC recurrence rates between therapy groups.Methods: In a retrospective cohort analysis among enrollees in managed care health plans, we identified female patients aged 55 years or older from 2004 to 2008 who were newly diagnosed with BC and had no evidence of prior BC surgery, chemotherapy, radiotherapy, or hormone therapy. Patients were followed from the date of first BC diagnosis until evidence of first (“index”) treatment with tamoxifen or an AI (anastrozole or letrozole). Outcomes of interest included differences between hormone therapy cohorts in patient characteristics (age, payer type) and clinical characteristics (risk group, Charlson comorbidity index [CCI]). Risk group was defined by treatments identified between the time of first BC diagnosis and index hormone therapy and included low (surgery only), medium (surgery and radiotherapy), higher (surgery then chemotherapy), and highest (neoadjuvant chemotherapy or combination surgery, radiotherapy, and chemotherapy). Unadjusted comparisons between cohorts were performed, with a p-value <0.05 considered statistically significant.Results: Of 4,191 newly diagnosed early BC patients identified, 950 (22.7%) received tamoxifen as first hormone therapy while 3,241 (77.3%) had evidence of AI therapy. There were no significant differences between therapy cohorts for geographic region or payer type, while differences in health plan type were marginally significant (p=0.05). Mean (median) age was 60.7 (59) years for tamoxifen patients and 61.4 (60) years for AI patients (p<0.001). Almost 60% of patients on AI therapy had 3 or more comorbidities as defined by the CCI compared to 45% of tamoxifen patients (p<0.001). Differences in the proportion of hormone therapy patients by risk group are provided in Table 1; compared to tamoxifen patients, a larger proportion of patients receiving AI therapy were found to be in the higher or highest risk groups (34.9% vs. 17.1%, p<0.001).Conclusion: According to real-world data, it appears that upfront AI therapy is the most widely used treatment option for early BC patients, regardless of risk group. The results indicate a tendency to use AI therapy significantly more often in patients defined as higher or highest risk. These baseline data are crucial in informing the design and statistical analyses of the next phase of this study to evaluate rates of early BC recurrence between therapy cohorts.Table 1. Hormone Therapy Patients by Risk Group.Risk GroupTamoxifen (N=950)AI Therapy (N=3,241)P-valueLow339 (35.7%)920 (28.4%)p=0.001Medium449 (47.3%)1,190 (36.7%) Higher57 (6.0%)416 (12.8%) Highest105 (11.0%)715 (22.1%) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2060.

Initial treatment and changes in adjuvant endocrine therapy for early stage breast cancer

Clinical trials have shown that aromatase inhibitors (AIs) are an important advance in the treatment of early stage breast cancer (ESBC), but practice patterns and the impact of treatment side effects of endocrine therapy in the community setting have not been extensively explored. This retrospective chart review describes practice patterns among patients receiving adjuvant endocrine therapy for ESBC. Charts of 200 patients with confirmed stage I–IIIA breast cancer were reviewed. Patients received first-line treatment with tamoxifen ( n = 96) or AIs ( n = 104). Fifty-one patients completed a structured interview regarding symptom burden during therapy. Time to discontinuation or switching from first-line therapy did not vary by drug class (tamoxifen vs. AI). Musculoskeletal symptoms predicted time to switching among AI patients. Tamoxifen patients who switched to AIs tended to do so following clinical guidelines for use of AIs. Interview results showed that more anastrozole than tamoxifen patients cited side effects as the reason for switching.

A randomised study comparing the effects of anastrozole (A), letrozole (L), exemestane (E) and tamoxifen (T) on coagulation.

Abstract Abstract #1132 Background:
 Aromatase inhibitors (AIs) reduce circulating oestrogens and so should have either no or a positive effect on coagulation . This study compares the effects of the non-steroidal aromatase inhibitors, A and L and the steroidal inactivator, E on coagulation.
 Patients and Methods:
 This was an open, randomized pharmacodynamic study. Plasma coagulation factors were measured in 120 postmenopausal women with invasive ER +ve breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive upfront therapy with either:
 16 weeks of A, 16 weeks of L or 16 weeks of E.
 Fasting blood samples were collected at entry and after 12 and 16 weeks of each drug. AI patients were then switched to T and further samples measured after 8 months on T.
 Plasminogen activator inhibitor (PAI) antigen, von Willebrand's Factor (vWF) antigen, antithrombin III (AT111), protein C, protein S total, protein S free, activated protein C, resistance (APCR), factor VIII and fibrinogen were measured.
 Results:
 Results expressed as % change from baseline.
 E vs A vs L
 Protein C. E caused a significant fall compared to A and L (-15.75 (-21.48, -10.02) vs -3.80 (-10.77, 3.16) vs -3.63 (-10.50, 3.25)) respectively. p = 0.008.
 ATIII. E caused a significant fall from baseline (-8.55 (-13.33, -3.79))
 Protein S Free. E + A caused a significant increase from baseline (E 6.90 (1.98, 11.82), A 7.36 (1.37, 13.34).
 Steroidal vs non-steroidal:
 Protein C. A significantly greater fall was seen with E than A+L (-15.75 (-21.45, -10.05) vs -3.71 (-8.58, 1.15)) p = 0.002.
 vWF A+L caused a significant increase from baseline (6.52 (0.66, 12.38) but this was not statistically different to E 5.02 (-1.88, 11.91)).
 ATIII A significant decrease from baseline was seen with A + L, -4.54 (-8.64, -0.43) but no difference from E 8.55 (13.31, -3.70) p=0.21.
 Protein S Free There was a significant increase from baseline in both groups (A+L: 5.70 (1.47, 9.92), E: 6.90 (1.98, 11.81), but no difference between the groups p=0.72.
 T effect:
 AT111 and protein C levels fell significantly on T whereas protein S free increased on T. Prior A, E or L had no significant impact on post-tamoxifen results.
 Conclusions:
 No significant differences in any coagulation factors were seen between A and L
 E caused a significant fall in protein C and ATIII.
 The non-steroidal AIs caused a significant increase in vWF.
 T caused a significant fall in protein C and ATIII and a significant increase in protein S free.
 No AI significantly influenced post-tamoxifen results.
 These drugs have significant effects on coagulation which helps to explain their clinical effects on thrombotic and thromboembolic disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1132.

Role of aromatase inhibitor in patients with poor response to clomiphene citrate needs further evaluation

Role of aromatase inhibitor in patients with poor response to clomiphene citrate needs further evaluation

Zoledronic acid: clinical potential beyond the prevention of skeletal complications in patients with cancer

Zoledronic acid has received international approval for the treatment of bone metastases and bone lesions from cancer. Phase III studies established the efficacy and safety profile of zoledronic acid in a broad range of tumor types. A direct comparison study with pamidronate demonstrated that zoledronic acid had a similar safety profile and provided superior clinical benefits in patients with breast cancer. Exploratory analyses of the large Phase III databases have demonstrated a survival benefit in patients with breast or lung cancer who achieved normalization of their biochemical marker of bone resorption, N-terminal telopeptide of Type I collagen, within 3 months of zoledronic acid therapy. Ongoing studies are evaluating zoledronic acid for the prevention of accelerated bone loss associated with aromatase inhibitors in patients with breast cancer and for the prevention of new bone metastases.

Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial

To compare the use of an aromatase inhibitor (letrozole) with the use of clomiphene citrate (CC). Prospective randomized study. An infertility clinic in a university hospital. Seventy-four consecutive infertile patients with polycystic ovary syndrome were recruited. Thirty-eight patients were randomized to the letrozole group (99 cycles), and the remaining patients were recruited to the CC group (95 cycles). The aromatase inhibitor letrozole (2.5 mg/d) and CC (100 mg/d) were administered orally on days 3-7 of menses. Number of follicles, endometrial thickness, E(2) levels on hCG day, and pregnancy rates among both groups. Ovulation occurred in 65.7% (65/99) of letrozole cycles and in 74.7% (71/95) of CC cycles. The median (minimum-maximum) number of follicles sized >15 mm in diameter on the day of hCG administration were 1 (0-4) and 1 (0-5) in the letrozole and CC groups, respectively. On the day of hCG administration, median serum E(2) concentrations in the letrozole and CC groups were statistically significantly different: 189 pg/mL (18-1,581 pg/mL) and 386 pg/mL (27-6,190 pg/mL), respectively. The median serum E(2) concentrations per follicle sized >15 mm in diameter on the day of hCG also statistically significantly differed between the letrozole and CC groups: 160 pg/mL (18-808 pg/mL) and 281 pg/mL (27-2,615 pg/mL), respectively. The median endometrial thickness on the day of hCG did not significantly differ between the CC and letrozole groups; it was 8 mm. Pregnancy was achieved in nine cycles (9.1%) of the letrozole group and in seven cycles (7.4%) of the CC group, which also was not a statistically significant difference. The aromatase inhibitor letrozole may be an acceptable alternative to CC as an ovulation-induction drug in patients with PCOS.

Inadvertent Use of Aromatase Inhibitors in Patients with Breast Cancer with Residual Ovarian Function: Cases and Lessons

Aromatase inhibitors (AIs) are important adjunctive therapy for postmenopausal women with hormone receptor— positive, early-stage breast cancer. At the present time, AIs have no role for the management of breast cancer in premenopausal women. We report on several cases of the inadvertent use of AI therapy among women with residual ovarian function. A common experience in these cases was the onset of chemotherapy-related amenorrhea before initiation of AI therapy, which confounded assessment of true menopausal status. We believe clinicians should be aware of the potential ovarian reserve among women with treatment-related amenorrhea so as to avoid use of AI therapy in patients in whom there is uncertainty about menopausal status.

Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ERalpha) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERalpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-I and epidermal growth factor receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERalpha, serves as the 'bus' which carries ERalpha to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.

Breast carcinomas with immunocytochemical detection of aromatase in fine-needle aspirates: Report of three cases

Three postmenopausal women with breast carcinoma underwent the fine-needle aspiration (FNA) preoperatively, and these specimens were stained by the antiaromatase antibody. We evaluated the identification of the aromatase immunoreactivity in breast carcinoma specimens obtained from both FNA and surgery. FNA specimens showed positive intracellular immunoreactivity of aromatase in these cases. The presence for aromatase in FNA specimens was identified with that in the surgical specimens. To our knowledge, the present cases are the first to report the aromatase staining of FNA specimens. The immunoreactivity of aromatase in FNA specimen may be useful to estimate the effectiveness of new aromatase inhibitors in patients with breast carcinoma. HUM PATHOL 32:348-351. Copyright © 2001 by W.B. Saunders Company

Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation

Studies using [ 3H]androstenedione (A) demonstrated that this substrate can be aromatized to estrone (E 1) in homogenates of breast carcinoma tissue and breast adipose tissue, in breast carcinoma and breast adipose stromal cells in culture, and in cultured adipose stromal cells from sites remote from the tumor. Using cultured breast carcinoma cells, it was shown that estrogen formation was stimulated by Cortisol (10 −6 M) and inhibited by endogenous 5α-reduced androgens: 5α-androstene-dione>androsterone>dihydrotestosterone>epiandrosterone>3α- and 3β-androstanediol. It was also shown that 19-nortestosterone and 19-norandrostenedione (10 −6 M) inhibited E 1 formation by 80%. Progesterone (10 −6 M) had no effect on aromatase activity, while the progestational agent R5020 (10 −6 M) caused a 70% inhibition. These studies emphasize that a variety of compounds can influence aromatase activity and that drugs which are used as aromatase inhibitors in patients with breast carcinoma may have multiple sites of action.