Tamoxifen Exemestane Adjuvant Multicentre Research Articles

Discordance between Immunohistochemistry and Erb-B2 Receptor Tyrosine Kinase 2 mRNA to Determine Human Epidermal Growth Factor Receptor 2 Low Status for Breast Cancer

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36-0.57), 0.58 (95% CI, 0.26-0.70), and 0.32 (95% CI, -0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization-negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials.

Targeted sequencing in a phase III trial of luminal breast cancer: Identification of novel targets.

505 Background: The International Cancer Genome Consortium and The Cancer Genome Atlas have had a global transformative impact on our understanding of cancer. These programs have mapped the genomic landscape of common and rare tumors setting the scene for a comprehensive change in the approach to cancer diagnosis and treatment. However, the task remains incomplete until these mutational events are linked to clinical outcomes in the context of current therapeutic intervention to drive future stratified medicine approaches. Methods: We performed targeted sequencing in patients from the Tamoxifen Exemestane Adjuvant Multicentre trial. DNA was extracted and a 101 gene panel analysed using a novel mutation calling pipeline. Both a priori and machine learning analyses were performed using distant recurrence free survival as the primary endpoint. Results: In 1,491 successfully analyzed samples 1,070 (71.76%) samples exhibited at least one single nucleotide mutation (range 0-94, 1.828+/-0.133, mean+/-s.e.). 98/101 genes were mutated in at least one patient. Only variants in PIK3CA, TP53, MLL3, CDH1 were detected in 5% or more of samples. Twenty genes were associated with increased risk of recurrence in multivariate analyses corrected for clinic-pathological variables, 50% of these genes were involved in transcriptional regulation or RNA/protein processing. In a multivariate analysis, two combined signalling modules were independently prognostic for residual risk following hormone therapy (HRvalidation 3.10 95%CI 1.78-5.40 and HRvalidation 2.70 95%CI 1.57-4.64). Conclusions: We successfully performed a signalling pathway-based targeted sequencing analysis within predefined signalling modules. In supervised and unsupervised analyses we identified multiple signalling cassettes linked to poor outcome in patients with ER+ve breast cancers treated with modern endocrine therapy in the context of a phase III clinical trial. These results identify novel candidates as targets to treat endocrine refractory breast cancers.

HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2

BackgroundA meta-analysis of the effects of HER2 status, specifically within the first 2–3 years of adjuvant endocrine therapy, has the potential to inform patient selection for upfront aromatase inhibitor (AI) therapy or switching strategy tamoxifen followed by AI. The pre-existing standardisation of methodology for HER2 (immunohistochemistry/fluorescence in situ hybridization) facilitates analysis of existing data for this key marker. MethodsFollowing a prospectively designed statistical analysis plan, patient data from 3 phase III trials Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC), Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre Trial (TEAM)] comparing an AI to tamoxifen during the first 2–3 years of adjuvant endocrine treatment were collected and a treatment-by-marker analysis of distant recurrence-free interval-censored at 2–3 years treatment – for HER2 status × AI versus tamoxifen treatment was performed to address the clinical question relating to efficacy of ‘upfront’ versus ‘switch’ strategies for AIs. ResultsA prospectively planned, patient-level data meta-analysis across 3 trials demonstrated a significant treatment (AI versus tamoxifen) by marker (HER2) interaction in a multivariate analysis; (interaction hazard ratio [HR] = 1.61, 95% CI 1.01–2.57; p < 0.05). Heterogeneity between trials did not reach statistical significance. The HER2 negative (HER2−ve) group gained greater benefit from AI versus tamoxifen (HR = 0.70, 95% CI 0.56–0.87) than the HER2-positive (HER2+ve) group (HR = 1.13, 95% CI 0.75–1.71). However, the small number of HER2+ve cases (n = 1092 across the 3 trials) and distant recurrences (n = 111) may explain heterogeneity between trials. ConclusionsA patient-level data meta-analysis demonstrated a significant interaction between HER2 status and treatment with AI versus tamoxifen in the first 2–3 years of adjuvant endocrine therapy. Patients with HER2−ve cancers experienced improved outcomes (distant relapse) when treated with upfront AI rather than tamoxifen, whilst patients with HER2+ve cancers fared no better or slightly worse in the first 2–3 years. However, the small number of HER2+ve cancers/events may explain a large degree of heterogeneity in the HER2+ve groups across all 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded and warrant further exploration.

Physical activity and survival of postmenopausal, hormone receptor-positive breast cancer patients: results of the Tamoxifen Exemestane Adjuvant Multicenter Lifestyle study.

Physical activity has been related to improved breast cancer outcomes. Especially in the older breast cancer population, physical activity may be important because old age is associated with comorbidities and decreased physical function. The purpose of this study was to investigate the relation between physical activity and overall survival, breast cancer-specific survival, and recurrence in several age groups of postmenopausal breast cancer patients. The Tamoxifen Exemestane Adjuvant Multinational Lifestyle study was a side study of the Tamoxifen Exemestane Adjuvant Multinational trial and prospectively investigated lifestyle habits of postmenopausal, hormone receptor-positive breast cancer patients. The relations between prediagnosis and postdiagnosis physical activity and overall survival, breast cancer-specific survival, and recurrence-free survival were assessed with Cox regression and competing risk regression models. Among 521 patients, high levels of physical activity before and after the diagnosis were associated with better overall survival (the multivariate hazard ratios were 0.50 [95% confidence interval = 0.26-0.98] and 0.57 (95% confidence interval = 0.26-1.40] for patients who were very active before and after the diagnosis, respectively, in comparison with inactive patients). This was most evident in patients who were 65 years old or older. Physical activity was not significantly associated with breast cancer-specific survival or the relapse-free period. Overall survival was better for patients who were active before and after the diagnosis. In contrast with previous studies, breast cancer survival and the risk of recurrence were not significantly associated with physical activity. These findings confirmed the need for more studies investigating the use of physical activity to supplement breast cancer treatment in older patients.

Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) Trial: results of a German substudy

ABSTRACTAim The aim of this study was to compare the effects of exemestane and tamoxifen on hormone levels in postmenopausal patients with hormone receptor-positive breast cancer within a Germany substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.Methods Within the TEAM trial, patients were randomized to receive adjuvant treatment with exemestane for 5 years or tamoxifen for 2.5–3 years followed by exemestane for 2–2.5 years. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)-intact were measured at screening and after 3, 6 and 12 months of treatment.Results Data on hormone levels were available from 63 patients in the tamoxifen arm and 68 patients in the exemestane arm. Treatment with exemestane resulted in decreases from baseline in SHBG and PTH-intact levels, and increases from baseline in testosterone, DHEAS and FSH levels. Tamoxifen treatment resulted in increases from baseline in SHBG and PTH-intact, whereas levels of testosterone and FSH decreased and DHEAS levels did not change. At all time points assessed, the absolute change from baseline was significantly different between tamoxifen and exemestane for testosterone, SHBG, FSH and PTH-intact (all p < 0.0001).Conclusions Exemestane and tamoxifen had statistically significantly different effects on hormone levels, including testosterone, SHBG, FSH and PTH-intact.

Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: Results of a prospective gynecological ultrasound substudy

Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: Results of a prospective gynecological ultrasound substudy

Adjuvant treatment of breast cancer in postmenopausal women: role of exemestane

Adjuvant hormonal therapy significantly reduces the risk of recurrence and death following surgery for estrogen receptor (ER)-positive early breast cancer. Previously, the gold standard hormonal therapy was tamoxifen, a selective modulator of the ER. However, large clinical trials conducted over the past decade have defined the efficacy of an alternative class of hormonal agent, namely the third-generation aromatase inhibitors (AIs): exemestane, letrozole, and anastrozole. On the basis of the pivotal International Exemestane Study (IES), exemestane, a steroidal third-generation AI, was licensed for the adjuvant treatment of postmenopausal women with ER-positive early breast cancer following 2-3 years of tamoxifen to complete a total of 5 years of adjuvant hormonal therapy. Here, we consider recent data to emerge primarily from the IES and Tamoxifen Exemestane Adjuvant Multicenter trials and consider their implications for the role of exemestane in the adjuvant treatment of breast cancer.

Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: Results of a prospective gynecological ultrasound substudy

Objectives This study prospectively assessed the effects of exemestane and tamoxifen on the endometrium in patients receiving adjuvant treatment for postmenopausal hormone receptor-positive breast cancer within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial. Methods Patients were randomized to receive tamoxifen or exemestane. In a prespecified trial subprotocol, patients underwent transvaginal ultrasound to assess endometrial thickness at baseline and during a 1- to 3-year treatment period. Results Among 143 evaluable patients, there were no cases of endometrial thickness > 10 mm with exemestane, vs. 11 cases with tamoxifen ( p < 0.0003). There was a significant difference between the treatment groups regarding time to endometrial thickness > 10 mm, in favour of exemestane ( p < 0.0001). Time to endometrial thickness > 5 mm was significantly longer for exemestane than for tamoxifen ( p < 0.0001). Median time to endometrial thickness > 5 mm or censoring was 583 days in the exemestane group versus 315 days in the tamoxifen group. There were also significantly fewer incidences of endometrial thickness > 5 mm at month 6 and month 12 with exemestane compared to tamoxifen (tamoxifen: 6% and 2%; exemestane: 29% and 39%, respectively). After 12 months, mean increases in endometrial thickness from baseline were 2.64 mm and 6.0 mm in the exemestane and tamoxifen groups, respectively ( p < 0.0006). Moreover, 17 histologically confirmed endometrial changes were observed in the tamoxifen group, vs. one in the exemestane group. Conclusions Exemestane was associated with significantly less endometrial thickening than tamoxifen during adjuvant endocrine therapy for postmenopausal hormone receptor-positive breast cancer.

Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy

Background: Adjuvant treatment of hormone receptor-positive breast cancer in postmenopausal women with aromatase inhibitors may be associated with increased bone loss.Patients and methods: Two hundred patients were randomised to receive exemestane or tamoxifen as adjuvant treatment of hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6 and 12 months treatment.Results: One hundred and sixty-one patients were assessable. Tamoxifen treatment resulted in a 0.5% increase from baseline in BMD at the spine, which was maintained at 12 months. Exemestane-treated patients experienced a 2.6% decrease from baseline in BMD at the spine at 6 months and a further 0.2% decrease at 12 months. There were significant differences in the changes in BMD between tamoxifen and exemestane at 6 and 12 months (P=0.0026 and P=0.0008, respectively). The mean changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen at 6 and 12 months (P = 0.0009 and P=0.04, respectively). There was no difference between tamoxifen and exemestane in mean changes in BMD from baseline at the femoral neck.Conclusions: Exemestane treatment resulted in an increase in bone loss at 6 months; bone loss stabilised after 6- to 12-month treatment.

The effect of exemestane or tamoxifen on markers of bone turnover: Results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial

Adjuvant treatment of breast cancer with aromatase inhibitors has been associated with increased bone loss. In this study, postmenopausal patients with oestrogen receptor positive breast cancer were randomised to exemestane for 5 years or tamoxifen for 2–2.5 years, followed by exemestane for 2–2.5 years. Levels of bone formation markers (bone specific alkaline phosphatase, amino terminal propeptide of type I procollagen, osteocalcin), and the bone resorption marker (carboxyterminal crosslinked telopeptide of type I collagen), were assessed at baseline and after 3, 6 and 12 months of treatment. Exemestane ( n = 78) resulted in increases from baseline in all bone turnover marker levels at all timepoints. In contrast, levels of all bone marker turnovers decreased with tamoxifen ( n = 83). Differences between tamoxifen and exemestane were statistically significant for all bone turnover markers at all timepoints. In conclusion, exemestane results in increases in markers of bone formation and resorption, while decreases are observed with tamoxifen.

Quality of life in relation to hormonal treatment of postmenopausal women in the Dutch Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Abstract Abstract #21 Background In the last decade, use of adjuvant hormonal treatment increased as well as its duration. Aromatase inhibitors are associated with a minimal increase of disease free survival compared to tamoxifen. Both therapies are associated with different side effects which can affect quality of life (QoL). Therefore, it is necessary to compare the QoL of patients using these therapies. We compared the QoL of women participating in the Dutch Tamoxifen Exemestane Adjuvant Multicentre (TEAM) Trial.&amp;#x2028; Patients and Methods The Dutch TEAM trial included 2754 postmenopausal early breast cancer patients who were randomised between five years of exemestane or 2.5-3 years of tamoxifen followed by 2.5-2 years of exemestane. A total of 742 patients were invited onto the QoL subprotocol. At one (T1) and two (T2) years after start of hormonal treatment, patients were ask to fill in questionnaires. This questionnaire contains the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and the EORTC BR23 questionnaires, supplemented with Functional Assessment of Cancer Therapy - Endocrine Subscale (FACT-ES) questions covering endocrine symptoms. The endpoint was the difference in QoL between patients receiving tamoxifen or exemestane.&amp;#x2028; Results Questionnaires were completed by 543 patients at T1 and 83% of these returned the questionnaire of T2. There were no significant differences in physical functioning, role functioning, cognitive functioning, emotional functioning, body image, breast symptoms, arm symptoms and endocrine symptoms between both treatment groups at T1 nor at T2. Patients receiving exemestane had significantly less sexual enjoyment (difference of 9 points on a 0-100 scale; p=0.004) and more insomnia (difference of 8 points; p=0.005) compared to patients receiving tamoxifen at T1. At T2, there was no statistically significant difference in sexual enjoyment (difference of 4 points; p=0.287). However, patients receiving exemestane reported significantly worse sexual functioning (difference of 5 points; p=0.020) and still more insomnia (difference of 8 points; p=0.004).&amp;#x2028; Conclusion Patients using exemestane reported less sexual enjoyment and more sexual functional problems than patients using tamoxifen. This may be explained by the fact that specific side effects of exemestane (e.g. vaginal dryness) can cause less sexual enjoyment which can result in a decreased sexual functioning. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 21.

Physical activity to maintain quality of life in breast cancer survivors in the Dutch Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Abstract Abstract #4089 Background: Lifestyle habits such as physical activity frequently change after a breast cancer diagnosis and may unfavorably affect quality of life (QoL) as well as breast cancer outcome.&amp;#x2028; Patients and Methods: In the Lifestyle side study of the TEAM trial, lifestyle and QoL questionnaires were filled out at approximately one year after starting hormonal therapy (T1) and again one year later (T2). The T1 questionnaire also included a retrospective assessment of pre-diagnosis lifestyle. Level of recreational physical activity was assessed as time engaged in walking, bicycling, gardening, and sports. Intensity values (METs) were assigned to each activity. The overall level of recreational physical activity was calculated by summing the MET-hours/week of all activities. QoL was assessed using the EORTC C30 and BR23 questionnaires, supplemented with FACT-ES questions covering endocrine symptoms.&amp;#x2028; Results: A total of 543 breast cancer patients returned the first questionnaire (response 73%), of whom 454 patients also returned the second questionnaire. Relatively high levels of pre-diagnosis recreational physical activity were observed (mean±SD: 10.4±8.0 hours/week), with approximately one hour per day spent on walking or cycling. The level of recreational physical activity decreased to 8.6±7.2 hrs/wk at T1 and was partly restored at T2 (mean±SD; 9.7±7.4 hrs/wk; p&amp;lt;0.01 for pre-diagnosis vs T1 and T1 vs T2).&amp;#x2028; Individuals in the lowest quartile of physical activity at T1 had a significantly worse QoL at T1 with respect to the domains of physical functioning, role functioning and sexual functioning, as compared to individuals in highest quartile of physical activity (difference of 9-15 points on a 0-100 scale; p&amp;lt;0.01). Similarly, individuals with a decrease of ≥15 MET-hrs/wk (equivalent to 1 hr/day of moderate-intensity activities on 5 days of the week) from pre-diagnosis to T1 also had a significantly worse QoL at T1 with respect to physical and role functioning, as compared to individuals with stable levels of physical activity (difference of 12-15 points; p&amp;lt;0.01). The least active group and the individuals with a strong decrease in physical activity also scored worse on fatigue (difference of 15 points on a 0-100 scale; p&amp;lt;0.01).&amp;#x2028; Overall, no clinically significant changes in QoL were observed from T1 to T2. However, individuals who increased their level of physical activity from T1 to T2 more frequently experienced improved physical functioning (p=0.03) and a decrease in fatigue (p=0.12).&amp;#x2028; Conclusions: In this population of relatively active postmenopausal breast cancer patients, being physically active is associated with better QoL. The temporal sequence of changes in both physical activity and QoL needs to be further studied, since physical activity may affect QoL and vice versa. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4089.

Effect of exemestane on bone turnover markers and bone mineral density (BMD): 2 year results of the Dutch/Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Abstract Abstract #1154 Background Aromatase inhibitors (AIs) given to women with early breast cancer may adversely affect bone metabolism. We studied the effect of exemestane (E) on bone mineral density (BMD) and bone turnover and compared it to the effect of tamoxifen (T) treatment in a group of women participating in the Dutch and Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. In this trial, postmenopausal women with hormone sensitive early breast cancer (n=3168) were randomised between 5 years E or 2½-3 years T followed by 2½-2 years of E.&amp;#x2028; Methods In this subprotocol, 87 women were followed for two years. Patients with bone diseases were excluded. Total hip and lumbar spine BMD were assessed at baseline and after 1 and 2 years. The bone resorption marker cross-linked telopeptide of type-I collagen (CTX) and the bone formation marker N-terminal propeptide of type I collagen (PINP) were measured in fasting serum at baseline and after 3, 6, 12 and 24 months.&amp;#x2028; Results At baseline, there was no difference in total hip (E: 0.85g/cm2, T: 0.80g/cm2; p=0.642) and lumbar spine BMD (E: 0.99g/cm2, T: 1.02g/cm2; p=0.545) between both groups. After 2 years, there were no significant changes in total hip BMD (E: 0.02 g/cm2 95%CI -0.05;0.08, p=0.849; T: 0.03 g/cm2, 95%CI -0.02;0.09, p=0.466) and in spine BMD (E: -0.02 g/cm2 95%CI -0.11;0.06, p=0.834; T: 0.02 g/cm2 95%CI -0.05;0.10, p=0.747). At baseline, there was no difference in serum CTX (E: 0.34ng/mL, T: 0.29ng/mL; p=0.271) and P1NP (E: 57ng/L, T:58ng/L, p=0.973) between both groups. After 2 years of treatment, serum CTX increased, although not significantly in the E group (20%, 95%CI -6%;54%, p=0.223) while it decreased significantly in the T group (-40%, 95%CI -23%;-53%, p&amp;lt;0.001). At 24 months, the CTX was 0. 44ng/mL (E) and 0. 18ng/mL (T). Serum P1NP did not change in the E group (-2%, 95%CI -20%;19%, p=0.837) but decreased significantly in the T group (-48%, 95%CI -36%;-58%, p&amp;lt;0.001). At 24 months, the P1NP was 55ng/L (E) and 28ng (T).&amp;#x2028; Conclusion Although there was a trend for an increase in bone resorption with E treatment, this was not significant and was not associated with a decrease in BMD. The magnitude of the reported negative effect of aromatase inhibitors on bone metabolism in studies using T as comparator treatment may be overestimated by the effect of T on bone turnover. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1154.

Comparison of Menopausal Symptoms During the First Year of Adjuvant Therapy With Either Exemestane or Tamoxifen in Early Breast Cancer: Report of a Tamoxifen Exemestane Adjuvant Multicenter Trial Substudy

Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor-positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.

A multidisciplinary team approach to family history risk assessment reduced clinic attendance by half

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36–0.57), 0.58 (95% CI, 0.26–0.70), and 0.32 (95% CI, −0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization–negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials.

Exemestane as Adjuvant Treatment of Early Breast Cancer: Intergroup Exemestane Study/Tamoxifen Exemestane Adjuvant Multicenter Trials

This review summarizes the status of 2 major clinical trials involving exemestane, a nonsteroidal inactivator of aromatase. The first trial, Intergroup Exemestane Study (IES), has been previously reported. More than 4700 postmenopausal women were randomized to receive exemestane versus continued tamoxifen at 2-3 years into 5 years of adjuvant tamoxifen. In the hormone receptor—positive group, there was a one-third improvement in disease-free survival and a near survival advantage ( P = 0.08) for the crossover strategy. The second trial is the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) study. Recently, the design was modified to take into account the information from the IES. In the initial phase of TEAM, 7000 patients were randomized to receive 5 years of exemestane versus 5 years of tamoxifen. With the IES results, TEAM was modified so that 5 years of exemestane would be compared with 5 years of tamoxifen crossed over to exemestane. An additional 2500 patients have now been accrued. Updates of the IES and the first report of the TEAM might be available in 2006. The implications of these studies are discussed in this article.