Adjuvant Chemo Endocrine Therapy
Vered Stearns
Nancy E. Davidson
INTRODUCTION
Adjuvant systemic therapy is associated with significant improvements in disease-free and overall survival benefits and is recommended to most women with stage I—III breast cancer. Adjuvant systemic therapy may include endocrine manipulation, cytotoxic therapy, anti-HER2 agents, or a combination of more than one of these approaches. The benefits and adverse effects associated with each of the individual treatments are discussed elsewhere in this textbook. As described in Chapter 43, endocrine therapies are recommended to most women with a tumor expressing the estrogen receptor α (ER) and/or progesterone receptor (PgR) proteins. The main challenge facing healthcare providers and women with newly diagnosed hormone receptor-positive tumors is to further determine who would benefit from the administration of chemotherapy in addition to endocrine manipulations, designated chemo endocrine therapy. Other questions pertain to the type, duration, and sequence of therapy that should be considered in this population. Notably, some women with hormone receptor-positive tumors are relatively resistant to endocrine manipulations, yet might not derive benefit from chemotherapy either. Identification of mechanisms and biomarkers of endocrine resistance will help in development of novel therapies that could be administered either with or instead of endocrine therapy. In this chapter, we review current considerations for administration of chemo endocrine therapy in properly selected women.
WHO IS A CANDIDATE FOR CHEMO ENDOCRINE THERAPY?
The presence of the hormone receptors ER and/or PgR is required for response to endocrine manipulations. However, not every woman whose tumor expresses the hormone receptors benefits from endocrine manipulations. Over the last two decades several analyses have helped provide guidance in the difficult task of separating women who would benefit from endocrine therapy alone from those for whom additional or alternative therapy is required.
Main Results from the Early Breast Cancer Trialists’ Collaborative Group Overview
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Overview of patient-level data from prospective randomized trials continues to provide the largest data set estimating impact of single or multi-agent adjuvant endocrine and chemotherapy regimens on survival outcomes in women with early breast cancer. The 2005 publication of the 2000 Overview included 194 studies of combination chemotherapy including CMF (cyclophosphamide, methotrexate, fluorouracil), FAC or CAF (fluorouracil, doxorubicin, cyclophosphamide), or FEC (fluorouracil, epirubicin, cyclophosphamide), and the endocrine therapies tamoxifen or ovarian ablation/suppression. Treatment with approximately 6 months of anthracycline-based polychemotherapy was significantly more effective than CMF in reducing breast cancer recurrence (2p = 0.0001) and mortality (2p = 0.00001) (1). The benefit was more substantial in women younger than 50 years of age, with a 38% (Standard Error [SE] 5%) reduction in annual breast cancer death rate compared to about 20% (SE 4%) for those ages 50 to 69. The differences were irrespective of ER status, use of tamoxifen, nodal status, or other tumor characteristics. The number of women older than age 70 who were included in the prospective studies was too small to allow for meaningful conclusions for this subgroup. In women whose tumors were ER-positive, 5 years of tamoxifen was associated with a substantial reduction in annual breast cancer recurrence and death irrespective of the use of chemotherapy, age, PgR status, or other tumor characteristics.
The Overview suggested that allocation to ovarian ablation or suppression (n = 8,000) also significantly reduced breast cancer recurrence and mortality. However, the benefit was seen primarily in women who have not received other systemic treatments (1).
The Overview suggested that allocation to ovarian ablation or suppression (n = 8,000) also significantly reduced breast cancer recurrence and mortality. However, the benefit was seen primarily in women who have not received other systemic treatments (1).
The most recent EBCTCG updates of relevant randomized trials shed further light on tamoxifen as well as newer chemotherapy regimens. In an overview of data from 20 trials (n = 21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, tamoxifen was associated with a substantial reduction of recurrence rates at 5 years (26.1% and 15.4% in control- and tamoxifentreated women, respectively) and 10 years (37.7% and 24.8% in control- and tamoxifen-treated women, respectively) (2). Although women were allocated to tamoxifen for only 5 years, the benefits were observed up to 15 years from the initial assignment, well beyond the duration of administration and emphasizing the importance of this agent.
In the most recent analysis of 123 randomized trials addressing chemotherapy questions, the trialists compared results with polychemotherapy versus no chemotherapy (n = 32,000), different anthracycline-containing regimens (n = 7,000), CMF-containing regimens (n = 18,000), or any taxane plus anthracycline-based combinations to regimens of nontaxane chemotherapy (n = 44,000) (3). A comparison of CMF for six cycles with the standard combination of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) for four cycles revealed equivalent breast cancer mortality rates (relative risk [RR] 0.98, SE 0.05; 2p = 0.67). However, the administration of anthracycline-based regimens that included a higher cumulative dose than standard AC, such as CAF or CEF, were superior to standard CMF (RR 0.78, SE 0.06; 2p = 0.0004). When comparing polychemotherapy to no chemotherapy, greater breast cancer mortality reductions were observed with CAF (RR 0.64, SE 0.09; 2p < 0.0001) compared to standard AC (RR 0.78, SE 0.09; 2p = 0.01) or CMF (RR 0.76, SE 0.05; 2p < 0.0001). Finally, the administration of four cycles of a taxane following an anthracycline-based regimen was associated with significant reduction in breast cancer mortality (absolute gain 2.8%, SE 0.9; RR 0.86, SE 0.04; 2p = 0.0005) when compared with the anthracycline-based regimen alone. In contrast, when taxanes added to anthracycline-based therapy without changing the duration of treatment in the investigational arms were compared to roughly doubling nontaxane agents’ dose in control arms, a significant difference in breast cancer mortality was not observed (RR 0.94, SE 0.06; 2p = 0.33). For all comparisons of taxane-based or anthracycline-based regimens, the EBCTCG noted that proportional risk reductions were independent of age, nodal status, tumor size, tumor differentiation, ER expression, or tamoxifen use. Subgroup analysis by ER status and subset analysis by expression, age, and differentiation in ER-positive tumors are presented in Table 45-1A, 45-1B and 45-1C.
TABLE 45-1A Subgroup Analyses of Breast Cancer Mortality by Treatment, Results from the EBCTCG Part A Any Anthracycline-Based Regimen versus Standard CMF (or Near-Standard CMF) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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While the EBCTCG provides substantial information regarding the value of specific therapies in reducing recurrence and mortality rates in women with early breast cancer, it is associated with several limitations. The Overview has not yet evaluated the role of newer agents such as thirdgeneration aromatase inhibitors or trastuzumab or dosedense anthracycline- and taxane-based regimens. Evidence regarding the benefit or harms of these newer agents or approaches is derived mostly from smaller meta-analyses or from large prospective randomized trials. Overview data regarding tumor or patient characteristics provide important information regarding odds of benefiting from endocrine strategies alone or whether additional agents should be considered. However, the Overview cannot provide data regarding benefits that an individual woman should expect from specific types of treatment or agents. Finally, there was no central review of ER, PgR, or other tumor characteristics in the Overview and results of new molecular analyses such as HER2 status or multigene assay results are not yet a part of the Overview. Nonetheless, the EBCTCG analyses have been pivotal in defining the benefits of adjuvant tamoxifen and chemotherapy for the population at large.
Meta-Analyses of Randomized Trials of Aromatase Inhibitors
A recent meta-analysis of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (Cohort 1) or after 2 to 3 years of tamoxifen
(Cohort 2) was also reported. Data submitted to the EBCTCG were used in separate meta-analyses of the two cohorts, which included postmenopausal women with ER-positive tumors (4).
(Cohort 2) was also reported. Data submitted to the EBCTCG were used in separate meta-analyses of the two cohorts, which included postmenopausal women with ER-positive tumors (4).
TABLE 45-1B Subgroup Analyses of Breast Cancer Mortality by Treatment, Results from the EBCTCG Part B Subgroup Analyses of Breast Cancer Mortality (Mortality with Recurrence, by Log-Rank Subtraction) for Taxane-plus-Anthracycline-Based Regimens versus the Same, or More (less than doubled or roughly doubled), Non-Taxane Cytotoxic Chemotherapy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Cohort 1 included data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 01-98 trials and was comprised of 9,856 patients with a mean of 5.8 years of follow-up. At 5 years, AI therapy was associated with an absolute decrease in recurrence of 2.9% (SE 0.7%, 9.6% for AI vs. 12.6% for tamoxifen; 2p < 0.00001) and in breast cancer mortality of 1.1% (SE 0.5%, 4.8% for AI vs. 5.9% for tamoxifen; 2p = 0.1).
TABLE 45-1C Subgroup Analyses of Breast Cancer Mortality by Treatment, Results from the EBCTCG Part C Any Anthracycline-Based Regimen versus No Chemotherapy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Cohort 2 consisted of four trials including German Adjuvant Breast Cancer Group/Arimidex-Nolvadex, Intergroup Exemestane Study/BIG 02-97, Italian Tamoxifen Anastrozole Trial (ITA), and Austrian Breast & Colorectal Cancer Study Group (ABCSG) 8, with a total of 9,015 women and a mean of 3.9 years of follow-up. At 3 years from treatment separation, AI therapy was associated with an absolute decrease in recurrence of 3.1% (SE 0.6%, 5.0% for AI vs. 8.1% for tamoxifen; 2p < 0.00001) and in breast cancer mortality of 0.7% (SE 0.3%, 1.7% for AI vs. 2.4% for tamoxifen; 2p = 0.02). The use of chemotherapy was not described in this analysis; however, review of the individual studies reveals that approximately 20% to 30% of participants received chemo endocrine therapy and these results are reviewed below. This meta-analysis confirms that use of an AI, administered instead of or in sequence with tamoxifen, is superior to use of tamoxifen alone in most postmenopausal women. This analysis helps to evaluate the role of AI instead of or in addition to tamoxifen, but unfortunately it does not provide specific guidance regarding the use of chemo endocrine therapy.
Prognostic and Predictive Markers
Clinicians use important tools, such as Adjuvant! Online, derived from and based on results from the Overview and other data sets, to provide estimates of recurrence and death and to predict response to specific treatments for their patients (5). However, increasing understanding of the molecular characteristics of individual tumors is expected to aid further in personalized treatment recommendations. The EBCTCG and AI meta-analyses have examined the role of prognostic and predictive markers that can be used to determine who would benefit from endocrine therapy alone, and who should be recommended chemo endocrine therapy. Prognostic factors reflect the natural biology of the tumor in the absence of systemic therapy and are used to estimate risk of recurrence (6, 7 and 8). In contrast, predictive factors reflect likelihood of benefit from specific treatments or agents. Most factors are both prognostic and predictive as reviewed in Chapter 28. Although initial investigations concentrated on single biomarkers such as ER, PgR, or markers of proliferation or differentiation, newer analyses are assessing the role of multiple markers simultaneously.
TABLE 45-2A Relevance of Quantitative Progesterone Receptor Measurement in Women with ER-Positive Tumors to Outcome by Allocated Treatment in Trials of about 5 Years of Adjuvant Tamoxifen or AI Part A Recurrence Rate Ratio for Tamoxifen versus Control in the EBCTCG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ER and PgR Status
The EBCTCG assessed benefit from tamoxifen versus not based on level of ER expression and PgR status. In 7,378 women with ER- and PgR-positive tumors, tamoxifen use led to a relative risk of recurrence at 10 years of 0.63 (95% Confidence Interval [CI], 0.58-0.68; Log-rank 2p < 0.00001) (1). A similar substantial benefit was observed in 2,310 women with ER-positive and PgR-poor tumors (RR 0.60, 95% CI, 0.52-0.69; Log-rank 2p < 0.00001) (Table 45-2A), and in women whose tumors were marginally ER-positive. No benefit was seen in those women whose tumors were ER-poor.
In Cohort 1 of the AI meta-analysis, a difference in outcome was observed with respect to PgR status in the 8,745 patients (89%) with a known PgR status. The proportional reduction in recurrence in AI compared to tamoxifen was 40% (SE 9%) in the 22% of women with ER-positive, PgR-poor tumors and 17% (SE 6%) in those with ER-positive, PgRpositive tumors (Table 45-2B). The authors noted, however, that the results could be attributed to chance alone given that the global test of heterogeneity was nonsignificant, the total number of subgroups was large, and the PgR-associated effect was seen only in one of the two trials (ATAC) (4). In Cohort 2, PgR status was known in 8,184 patients (91%), and was associated with a similar proportional reduction in recurrence in women with ER-positive, PgR-poor disease (37%, SE 12%) and those with ER-positive, PgR-positive disease (21%, SE 8%) (Table 45-2B). No significant difference was seen between the groups, regardless of PgR status, age, nodal status, and tumor grade, and the global test of heterogeneity for the subgroup analyses was negative.
The role of PgR in determining response to endocrine therapy alone was also examined in several studies that have consistently demonstrated superior benefit for women whose tumors contain both ER and PgR compared to those with ER-positive, PgR-poor tumors (9, 10 and 11). One of the largest cohorts included two databases, the first consisting of 3,739 patients who did not receive adjuvant systemic therapy and 1,688 patients who received adjuvant endocrine therapy alone, and the second consisting of 10,444 patients who received adjuvant endocrine therapy alone and whose tumors were subjected to central biochemical ER and PgR testing. The majority of women (>95%) received tamoxifen. PgR status was associated with disease-free and overall
survival in endocrine therapy-treated patients, and was independent of nodal status, tumor size, and age. Compared to women with ER- and PgR-negative tumors as a baseline, the relative risk of recurrence and death was reduced more substantially in women with ER-positive, PgR-positive tumors than in those with ER-positive, PgR-negative tumors (p < .0001), suggesting that women whose tumors express both hormone receptors derive more benefit from endocrine therapy, primarily tamoxifen (9). Since these data sets excluded women who received chemotherapy, this study cannot answer whether women whose tumors are PgRnegative derive preferential benefit from chemo endocrine therapy compared to those whose tumors are PgR-positive. However, given a reduced benefit from endocrine therapy alone compared to women whose tumors contain both hormone receptors, women with ER-positive, PgR-negative tumors may be candidates for chemo endocrine therapy.
survival in endocrine therapy-treated patients, and was independent of nodal status, tumor size, and age. Compared to women with ER- and PgR-negative tumors as a baseline, the relative risk of recurrence and death was reduced more substantially in women with ER-positive, PgR-positive tumors than in those with ER-positive, PgR-negative tumors (p < .0001), suggesting that women whose tumors express both hormone receptors derive more benefit from endocrine therapy, primarily tamoxifen (9). Since these data sets excluded women who received chemotherapy, this study cannot answer whether women whose tumors are PgRnegative derive preferential benefit from chemo endocrine therapy compared to those whose tumors are PgR-positive. However, given a reduced benefit from endocrine therapy alone compared to women whose tumors contain both hormone receptors, women with ER-positive, PgR-negative tumors may be candidates for chemo endocrine therapy.
TABLE 45-2B Relevance of Quantitative Progesterone Receptor Measurement in Women with ER-Positive Tumors to Outcome by Allocated Treatment in Trials of about 5 Years of Adjuvant Tamoxifen or AI Part B Recurrence Rate Ratio for Aromatase Inhibitor versus Tamoxifen in the AI Meta-Analysis | |||||||||||||||||||||||||||||||||||||||||||||||
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A comprehensive review of the role of ER and PgR in breast cancer is provided in Chapter 27. In aggregate, available data provide a strong rationale for the consideration of endocrine therapy in every woman with an invasive cancer that contains ER or PgR expression at any level. Indeed, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) International Expert Panel recommended that ER and PgR immunohistochemistry (IHC) assays should be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of proper internal and external controls (12). This would then trigger a discussion about the value of adjuvant endocrine therapy.
ER and PgR assessment by IHC alone, however, may not be useful in determining who should also be advised to receive chemotherapy. Overall the data suggest that women with tumors lacking PgR may suffer inferior benefit with endocrine therapy alone compared to women whose tumors express both hormone receptors, and for those women additional evaluation of the tumor may be considered prior to making recommendations regarding chemotherapy use. Newer methods may enable better determination of quantitative ER and PgR expression. Assessment of the functional status of the ER, optimal balance of coactivators and corepressors, and crosstalk between ER and growth factor signaling may be available in the future and could perhaps allow prediction of response to endocrine therapy or requirement for alternative or additional therapies. It is likely, however, that the presence and strength of hormone receptor expression correlates with intrinsic tumor subtypes, as described below, and that newer, more comprehensive assays may be more informative in selecting women who should consider chemo endocrine therapy.
Tumor Differentiation and Markers of Proliferation
Historically, poor differentiation or a high tumor grade or proliferative index has been associated with inferior prognosis in the absence of treatment, an improved response to cytotoxic therapy, and a poor response to endocrine therapy. In the Overview, information regarding tumor differentiation and outcome was available from approximately 47% of all tumors. The proportional risk reductions produced by chemotherapy in each of the differentiation categories were statistically similar (Table 45-3A) (3). In the AI meta-analysis, subgroup analyses of the recurrence results based on grade showed no significant difference (Table 45-3B) (4). However, as is the case with hormone receptor status, central review of grade was not conducted in either the EBCTCG or the AI meta-analyses.
Most other evaluations assessing grade, differentiation, or other proliferation factors are also retrospective in nature, but collectively they suggest that highly proliferative tumors are associated with a relative endocrine resistance and enhanced sensitivity to cytotoxic therapy, thus supporting chemo endocrine approaches. As is the case with other individual biomarkers, the use of assays that allow for multi-gene assessment may be more informative than tumor grade in determining relative responsiveness or resistance to endocrine therapy.
Growth Factors and Other Tyrosine Kinase Receptors
As we noted previously, chemo endocrine therapy has been recommended to women with ER-positive tumors that are associated with biomarkers predictive of endocrine resistance. Suggested mechanisms of endocrine resistance include activation of downstream regulatory molecules in other growth factor signaling pathways such as epidermal growth factor (EGFR, HER1) and human epidermal growth factor receptor 2 (HER2), expression of other tyrosine kinase receptors, and alterations in the balance of coregulators (13).
Cross-talk between the ER and HER1 and HER2 has been implicated as a predictor of relative resistance to endocrine manipulations in several preclinical and clinical
investigations (14). In addition, ER-positive, PgR-negative tumors are often associated with overexpression of HER1 or HER2 compared to tumors expressing both ER and PgR. The expression of HER1 and overexpression of HER2 in ER-positive, PgR-negative but not in ER-positive, PgR-positive tumors predicted tamoxifen resistance and a high risk of recurrence (15). Recent results from studies in advanced breast cancer clearly demonstrate that the addition of an anti-HER2 agent to an AI is associated with improved progression-free survival (PFS) and provide rationale for studies in the adjuvant setting. In TAnDEM, postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer were randomly assigned to firstline anastrozole with or without trastuzumab. The combination was associated with improved PFS compared to anastrozole alone (Hazard Ratio [HR] 0.63; 95% CI, 0.47-0.84; median PFS 4.8 vs. 2.4 months; Log-rank p = .0016) (16). In a second study in a similar population, women were randomly assigned to letrozole with or without lapatinib. The combination was associated with superior PFS (HR 0.71; 95% CI, 0.53-0.96; p = .019; median PFS 8.2 vs. 3.0 months) (17). Small underpowered studies have provided conflicting results regarding the role of AI and EGFR tyrosine kinase inhibitors. PFS was longer in patients receiving the combination of anastrozole and the EGFR inhibitor gefitinib compared to those receiving anastrozole plus placebo (HR 0.55; 95% CI, 0.32-0.94; median PFS 14.7 vs. 8.4 months) (18), but other studies suggested that the likely benefit from EGFR inhibition added to AI or fulvestrant is small and not likely to outweigh increased toxicity (19).
investigations (14). In addition, ER-positive, PgR-negative tumors are often associated with overexpression of HER1 or HER2 compared to tumors expressing both ER and PgR. The expression of HER1 and overexpression of HER2 in ER-positive, PgR-negative but not in ER-positive, PgR-positive tumors predicted tamoxifen resistance and a high risk of recurrence (15). Recent results from studies in advanced breast cancer clearly demonstrate that the addition of an anti-HER2 agent to an AI is associated with improved progression-free survival (PFS) and provide rationale for studies in the adjuvant setting. In TAnDEM, postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer were randomly assigned to firstline anastrozole with or without trastuzumab. The combination was associated with improved PFS compared to anastrozole alone (Hazard Ratio [HR] 0.63; 95% CI, 0.47-0.84; median PFS 4.8 vs. 2.4 months; Log-rank p = .0016) (16). In a second study in a similar population, women were randomly assigned to letrozole with or without lapatinib. The combination was associated with superior PFS (HR 0.71; 95% CI, 0.53-0.96; p = .019; median PFS 8.2 vs. 3.0 months) (17). Small underpowered studies have provided conflicting results regarding the role of AI and EGFR tyrosine kinase inhibitors. PFS was longer in patients receiving the combination of anastrozole and the EGFR inhibitor gefitinib compared to those receiving anastrozole plus placebo (HR 0.55; 95% CI, 0.32-0.94; median PFS 14.7 vs. 8.4 months) (18), but other studies suggested that the likely benefit from EGFR inhibition added to AI or fulvestrant is small and not likely to outweigh increased toxicity (19).
TABLE 45-3A Relevance of Tumor Differentiation for ER-Positive Patients to Outcome by Allocated Treatment in Trials of about 5 Years of Adjuvant Tamoxifen or AI Part A Tamoxifen Versus Control Recurrence Rate Ratio in the EBCTCG | |||||||||||||||||||||||||||||
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TABLE 45-3B Relevance of Tumor Differentiation for ER-Positive Patients to Outcome by Allocated Treatment in Trials of about 5 Years of Adjuvant Tamoxifen or AI Part B Aromatase Inhibitor versus Tamoxifen Recurrence Rate Ratio in the AI Meta-Analysis | |||||||||||||||||||||||||||||||||||||||||||||||
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Activation of other tyrosine kinase receptors may also predict for a more aggressive tumor phenotype and relative resistance to endocrine therapy. In these situations, although the estrogen-dependent growth is inhibited via endocrine manipulations, other growth signals stimulate proliferation and lead to relative endocrine resistance. Activation of other growth signals is usually associated with higher grade tumors and those women have traditionally been offered chemo endocrine therapy (20, 21). Emerging results in the advanced, acquired endocrine-resistance disease setting provide strong support for prospective studies of novel targeted agents in the adjuvant setting in tumors with de novo endocrine resistance and are summarized in the “Future Directions” section of this chapter.
Molecularly Defined Tumor Subtypes
In the last decade emphasis has been given to designating tumors not only by their ER and PgR status but also by using a more careful determination of their intrinsic subtype. Initial gene expression analysis led to the recognition that several tumor subtypes exist and these carry differential prognostic and predictive implications (22). Tumors that
express ER or PgR may be Luminal A or B, or fall into the HER2 subtype. Luminal A tumors are generally associated with a high expression of ER, expression of PgR, and a low proliferation profile. Women with this tumor subtype are expected to derive benefit from endocrine manipulations. In contrast, Luminal B tumors, although ER-positive, are more likely to lack PgR and are associated with high proliferation indices. Luminal B tumors are more likely to be resistant to endocrine manipulations alone and women with this tumor subtype may benefit from chemo endocrine therapy.
express ER or PgR may be Luminal A or B, or fall into the HER2 subtype. Luminal A tumors are generally associated with a high expression of ER, expression of PgR, and a low proliferation profile. Women with this tumor subtype are expected to derive benefit from endocrine manipulations. In contrast, Luminal B tumors, although ER-positive, are more likely to lack PgR and are associated with high proliferation indices. Luminal B tumors are more likely to be resistant to endocrine manipulations alone and women with this tumor subtype may benefit from chemo endocrine therapy.
In the clinic, several assays can aid in classification of individual tumors to intrinsic subtypes and thus in treatment recommendations. A more comprehensive overview of the role of molecular prognostic and predictive markers is provided in Chapter 30. The most commonly used commercial assay is Oncotype DX. The assay includes 21 prospectively selected genes (16 cancer-related genes and 5 housekeeping genes) that are performed via reverse-transcriptase-polymerasechain-reaction (RT-PCR) on paraffin-embedded tumor tissue in a central laboratory. The expression of each of the genes is evaluated and tabulated using a proprietary formula and reduced to a single Recurrence Score. The assay was initially developed and validated in trials that included women with T1-2, node-negative, hormone receptor-positive tumors and is commercially available for women meeting these general criteria (23, 24). Although the Recurrence Score is continuous, it is further categorized as low, intermediate, or high. Tumors with low Recurrence Score are likely hormone-sensitive and chemotherapy does not appear to offer significant benefit. In contrast, tumors with high Recurrence Scores are relatively hormone-resistant and chemotherapy should be strongly considered. The initial studies suggest that women with tumors scoring in the intermediate range are also not likely to benefit from chemotherapy but were constrained by small sample size. It is anticipated that the prospective study, Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx, which has recently completed accrual, will help provide true estimates of risk with endocrine therapy alone or in combination with chemotherapy.
Related posts:
Breast Cancer Screening
Ductal Carcinoma In Situ and Other Intraductal Lesions: Pathology, Immunohistochemistry, and Molecular Alterations
Postmastectomy Radiation Therapy
Preoperative Endocrine Therapy for Operable Breast Cancer
Management Summary for the Care of Patients with Metastatic Breast Cancer
Nursing Care in Patient Management and Quality of Life
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