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Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays
References 1. Rouëssé J, de la Lande B, Bertheault-Cvitkovic F, et al: A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: Final results. Int J Radiat Oncol Biol Phys 64:1072-1080, 2006. 2. Toledano A, Garaud P, Serin D, et al: Concurrent administration of adjuvant chemotherapy and radiotherapy after breastconserving surgery enhances late toxicities: Long-term results of the ARCOSEIN multicenter randomized study. Int J Radiat Oncol Biol Phys 65:324-332, 2006. 3. Bellon JR, Come SE, Gelman RS, et al: The sequencing of chemotherapy and radiation therapy in early stage breast cancer: Updated results of a randomized trial. J Clin Oncol 23:19341940, 2005. 4. Calais G, Serin D, Fourquet A, et al: Randomized study comparing adjuvant radiotherapy (RT) with concomitant chemotherapy (CT) versus sequential treatment after conservative surgery for patients with stages I and II breast carcinoma (abstract 95). Int J Radiat Oncol Biol Phys 54:57-58, 2002. 5. Recht A, Come SE, Gelman RS, et al: Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage node-positive breast cancer: Sequencing, timing, and outcome. J Clin Oncol 9:1662-1667, 1991. 6. Bellon JR, Shulman LN, Come SE, et al: A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma. Cancer 100:1358-1364, 2004.
Weekly Cisplatin, Epirubicin, and Paclitaxel With Granulocyte Colony-Stimulating Factor Support vs Triweekly Epirubicin and Paclitaxel in Locally Advanced Breast Cancer: Final Analysis of a SICOG Phase III Study
outcome. Additionally, the study had 2 completely different amounts of epirubicin and paclitaxel being given in the 2 arms (epirubicin 360 vs 600 mg/m2 and paclitaxel 700 vs 40 mg/m2). As a result, it was hard to tell whether the increase in pCR rates was due to the addition of cisplatin, the dosages given, or the schedule of administration. In addition, no correlative studies were included that could help identify subsets of patients with a better response. The number of pCRs was disappointingly low, which is another criticism of the study. A pCR rate of 31% was reported in HER2positive tumors, whereas other studies have reported pCR rates of 50% to 70%, particularly with the use of trastuzumab.1,2 Trastuzumab has not been used in HER2-positive breast cancer at all, which adds to the weakness of the study. Although the results of this study are important, clinical practice is unlikely to change. It is interesting to note that the PET arm induced a pCR rate of 27.5% in estrogen receptor–negative cancers, which may indicate that it is an effective drug in triple-negative breast cancer. S. Glück, MD, PhD
References 1. Hurley J, Doliny P, Reis I, et al: Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J Clin Oncol 24:1831-1838, 2006. 2. Buzdar AU, Ibrahim NK, Francis D, et al: Signficantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676-3685, 2005.
Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays Regan MM, Viale G, Mastropasqua MG, et al
Frasci G, D’Aiuto G, Comella P, et al
J Natl Cancer Inst 98:1571-1581, 2006
Br J Cancer 95:1005-1012, 2006
This interesting study demonstrated that the assessment of estrogen receptor (ER) and progesterone receptor (PgR) status by immunohistochemical analysis is equal to traditional extraction assays in predicting response to adjuvant hormonal therapies in patients with node-negative breast cancer and is perhaps even better in certain subsets of patients. A particular strength of this study was the large sample size (n = 1,547) derived from pre- and postmenopausal patients enrolled in 2 international randomized clinical trials, providing excellent power to identify significant results that could be generalized to patients of all ages. Another strength was the use of standardized, high-quality immunohistochemical assays performed in a single-expert laboratory and the accurate scoring of the slides by counting at least 2,000 randomly selected tumor cells reported as percent positive. However, despite going to great and admirable efforts to quantify the results as a continuous variable, they were simply dichotomized into positive (any cells staining) and negative (no cells staining) in the final outcome analyses. Breast cancers vary greatly in receptor content, and there is a direct correlation be-
The study by Frasci and colleagues tested the efficacy of a more conventional epirubicin and paclitaxel (ET) combination given every 3 weeks for 4 cycles versus a weekly epirubicin and paclitaxel plus cisplatin (PET) schedule. The results showed that there was an increase in toxicity with PET. Significantly more pathologic complete responses (pCR) were reported in the PET arm compared to the ET arm (28% vs 19%, respectively), which was mainly seen in patients with estrogen receptor–negative tumors (27.5% vs 5.4%, respectively) and HER2-positive tumors (31% vs 5%, respectively). Time-dependent endpoints like time to progression and overall survival were not significantly different between treatment arms. This study has some limitations and attempted to ask too many questions at the same time. One question was whether the addition of cisplatin to an epirubicin and paclitaxel regimen was of any benefit. The second question was whether the delivery of chemotherapy in a weekly versus every-3-week schedule resulted in a different
®
Breast Diseases: A Year Book Quarterly Vol 18 No 3 2007
311 311
tween content and the likelihood of responding to hormonal therapies, so it was somewhat disappointing to see this useful information discarded. The extraction assays used in the study, which are inherently difficult, were of diverse types and performed in many laboratories, so their overall quality may be less than the IHC assays with which they were compared. However, major problems seem unlikely because the predictive abilities of the assays were so similar overall. In conclusion, the clinical results of this study confirm several previous investigations conducted during the past 10 years. Nonetheless, they are important because they are based on large randomized clinical trials and because they re-emphasize the importance of high-quality immunohistochemical analysis. The ability of immunohistochemical analysis to accurately measure ER and PgR is being hotly contested, and this study is a timely and powerful demonstration that this methodology produces excellent results when performed properly. I. D. Nagtegaal, MD, PhD D. C. Allred, MD
Survival With Aromatase Inhibitors and Inactivators Versus Standard Hormonal Therapy in Advanced Breast Cancer: Meta-Analysis Mauri D, Pavlidis N, Polyzos NP, et al J Natl Cancer Inst 98:1285-1291, 2006 Undeniably, a new standard of care in oncology is set when a change in practice improves survival durations. Because individual trials that compared an aromatase inhibitor with tamoxifen or a progestin in the advanced-disease setting did not consistently demonstrate an overall survival advantage, some have argued that the role of these agents as the first choice for advanced disease has not been completely established, even though improvements in the progressionfree intervals have been a fairly consistent feature of most of the studies reported.1 Mauri and colleagues therefore conducted a meta-analysis of 23 trials to address the survival effects of aromatase inhibitors further. They reported that the use of a thirdgeneration aromatase inhibitor (vorozole, letrozole, exemestane, or anastrozole) resulted in an 11% increase in survival over tamoxifen in the first-line setting. In addition, a 14% increase in survival over a progestin (medroxyprogesterone acetate and megestrol acetate) was observed in the second or subsequent lines of therapy for patients with advanced breast cancer. The enhanced potency of the third-generation aromatase inhibitors seemed to matter because the trials that involved first- and second-generation aromatase inhibitors failed to exhibit these modest survival advantages. Although an 11% to 14% improvement in the hazard ratio translates into only a few months of enhanced survival, time is a precious commodity for patients with advanced breast cancer, and these data will probably persuade the few remaining tamoxifen and progestin aficionados to finally switch to using aromatase inhibitors as upfront therapy. However, tamoxifen and other hormonal therapy agents remain important therapeutic options either as part of a sequential hormonal treatment strategy or as first-line therapy for breast cancer that has relapsed while the patient is taking an aromatase inhibitor as adjuvant therapy. C. X. Ma, MD, PhD M. J. Ellis, MB, PhD
312 312
®
Breast Diseases: A Year Book Quarterly Vol 18 No 3 2007
Reference 1. Wong ZW, Ellis MJ: First-line endocrine treatment of breast cancer: Aromatase inhibitor or antioestrogen? Br J Cancer 90:20-25, 2004.
A Prospective, Longitudinal Study of the Functional Status and Quality of Life of Older Patients With Breast Cancer Receiving Adjuvant Chemotherapy Hurria A, Hurria A, Zuckerman E, et al J Am Geriatr Soc 54:1119-1124, 2006 Clinicians are often faced with difficult decisions regarding recommendations for adjuvant chemotherapy in elderly women with breast cancer. In light of medical comorbidities, does the potential for increased toxicity outweigh the disease-free and overall survival benefits? Hurria and colleagues followed elderly patients receiving adjuvant chemotherapy for breast cancer and specifically examined this risk-benefit ratio. Older patients with newly diagnosed early breast cancer treated with standard adjuvant chemotherapy regimens were functionally assessed utilizing accepted geriatric tools of functional assessments. The median age of participants on this study was described as “younger elderly” at age 68 years, but the range of ages (65-84 years) is typical of older patients seen in busy oncology practices. Therefore, information gleaned from this study is useful for treatment planning. Albeit because the authors were located at a well-known tertiary referral center, the patients included in this clinical trial could be somewhat self-selected in that they have the support and ability to seek out specialized care. One would expect that such patients would possess a higher functional status. Therefore, an inherent selection bias may exist. Nevertheless, it is still very gratifying that despite approximately half of the patients experiencing the expected chemotherapy-associated toxicities, there was no significant decline in longitudinal quality of life. This population did not seem to lose functional status. This study is important because it highlights the possibility of bias that we as physicians display when faced with treating an older patient in the same manner as we would approach a younger patient (age less than 50 years). The idea of clinician bias is further supported by the fact that an Intergroup Trial, CALGB 49907, an adjuvant study randomizing patients aged 65 years or greater to treatment with either doxorubicin and cyclophosphamide or cyclophosphamide, methotrexate, and 5-fluorouracil versus oral capecitabine, has not been able to meet accrual for the past several years. This is despite the fact that the majority of patients with breast cancer eligible for chemotherapy are older and that data suggest that, if offered, older women are likely to accept adjuvant chemotherapy recommendations and enroll in adjuvant therapeutic clinical trials.1,2 Because of advances in the standard of living as well as the successes of modern and preventative medicine, the older population is increasing and will continue to enjoy good health and functionality. Therefore, looking forward, potentially larger numbers of patients can be expected to be included in the category of “the elderly” and may be candidates for curative, definitive adjuvant therapy. Although the numbers of patients in this prospectively acquired
Weekly Cisplatin, Epirubicin, and Paclitaxel With Granulocyte Colony-Stimulating Factor Support vs Triweekly Epirubicin and Paclitaxel in Locally Advanced Breast Cancer: Final Analysis of a SICOG Phase III Study
outcome. Additionally, the study had 2 completely different amounts of epirubicin and paclitaxel being given in the 2 arms (epirubicin 360 vs 600 mg/m2 and paclitaxel 700 vs 40 mg/m2). As a result, it was hard to tell whether the increase in pCR rates was due to the addition of cisplatin, the dosages given, or the schedule of administration. In addition, no correlative studies were included that could help identify subsets of patients with a better response. The number of pCRs was disappointingly low, which is another criticism of the study. A pCR rate of 31% was reported in HER2positive tumors, whereas other studies have reported pCR rates of 50% to 70%, particularly with the use of trastuzumab.1,2 Trastuzumab has not been used in HER2-positive breast cancer at all, which adds to the weakness of the study. Although the results of this study are important, clinical practice is unlikely to change. It is interesting to note that the PET arm induced a pCR rate of 27.5% in estrogen receptor–negative cancers, which may indicate that it is an effective drug in triple-negative breast cancer. S. Glück, MD, PhD
References 1. Hurley J, Doliny P, Reis I, et al: Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J Clin Oncol 24:1831-1838, 2006. 2. Buzdar AU, Ibrahim NK, Francis D, et al: Signficantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676-3685, 2005.
Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays Regan MM, Viale G, Mastropasqua MG, et al
Frasci G, D’Aiuto G, Comella P, et al
J Natl Cancer Inst 98:1571-1581, 2006
Br J Cancer 95:1005-1012, 2006
This interesting study demonstrated that the assessment of estrogen receptor (ER) and progesterone receptor (PgR) status by immunohistochemical analysis is equal to traditional extraction assays in predicting response to adjuvant hormonal therapies in patients with node-negative breast cancer and is perhaps even better in certain subsets of patients. A particular strength of this study was the large sample size (n = 1,547) derived from pre- and postmenopausal patients enrolled in 2 international randomized clinical trials, providing excellent power to identify significant results that could be generalized to patients of all ages. Another strength was the use of standardized, high-quality immunohistochemical assays performed in a single-expert laboratory and the accurate scoring of the slides by counting at least 2,000 randomly selected tumor cells reported as percent positive. However, despite going to great and admirable efforts to quantify the results as a continuous variable, they were simply dichotomized into positive (any cells staining) and negative (no cells staining) in the final outcome analyses. Breast cancers vary greatly in receptor content, and there is a direct correlation be-
The study by Frasci and colleagues tested the efficacy of a more conventional epirubicin and paclitaxel (ET) combination given every 3 weeks for 4 cycles versus a weekly epirubicin and paclitaxel plus cisplatin (PET) schedule. The results showed that there was an increase in toxicity with PET. Significantly more pathologic complete responses (pCR) were reported in the PET arm compared to the ET arm (28% vs 19%, respectively), which was mainly seen in patients with estrogen receptor–negative tumors (27.5% vs 5.4%, respectively) and HER2-positive tumors (31% vs 5%, respectively). Time-dependent endpoints like time to progression and overall survival were not significantly different between treatment arms. This study has some limitations and attempted to ask too many questions at the same time. One question was whether the addition of cisplatin to an epirubicin and paclitaxel regimen was of any benefit. The second question was whether the delivery of chemotherapy in a weekly versus every-3-week schedule resulted in a different
®
Breast Diseases: A Year Book Quarterly Vol 18 No 3 2007
311 311
tween content and the likelihood of responding to hormonal therapies, so it was somewhat disappointing to see this useful information discarded. The extraction assays used in the study, which are inherently difficult, were of diverse types and performed in many laboratories, so their overall quality may be less than the IHC assays with which they were compared. However, major problems seem unlikely because the predictive abilities of the assays were so similar overall. In conclusion, the clinical results of this study confirm several previous investigations conducted during the past 10 years. Nonetheless, they are important because they are based on large randomized clinical trials and because they re-emphasize the importance of high-quality immunohistochemical analysis. The ability of immunohistochemical analysis to accurately measure ER and PgR is being hotly contested, and this study is a timely and powerful demonstration that this methodology produces excellent results when performed properly. I. D. Nagtegaal, MD, PhD D. C. Allred, MD
Survival With Aromatase Inhibitors and Inactivators Versus Standard Hormonal Therapy in Advanced Breast Cancer: Meta-Analysis Mauri D, Pavlidis N, Polyzos NP, et al J Natl Cancer Inst 98:1285-1291, 2006 Undeniably, a new standard of care in oncology is set when a change in practice improves survival durations. Because individual trials that compared an aromatase inhibitor with tamoxifen or a progestin in the advanced-disease setting did not consistently demonstrate an overall survival advantage, some have argued that the role of these agents as the first choice for advanced disease has not been completely established, even though improvements in the progressionfree intervals have been a fairly consistent feature of most of the studies reported.1 Mauri and colleagues therefore conducted a meta-analysis of 23 trials to address the survival effects of aromatase inhibitors further. They reported that the use of a thirdgeneration aromatase inhibitor (vorozole, letrozole, exemestane, or anastrozole) resulted in an 11% increase in survival over tamoxifen in the first-line setting. In addition, a 14% increase in survival over a progestin (medroxyprogesterone acetate and megestrol acetate) was observed in the second or subsequent lines of therapy for patients with advanced breast cancer. The enhanced potency of the third-generation aromatase inhibitors seemed to matter because the trials that involved first- and second-generation aromatase inhibitors failed to exhibit these modest survival advantages. Although an 11% to 14% improvement in the hazard ratio translates into only a few months of enhanced survival, time is a precious commodity for patients with advanced breast cancer, and these data will probably persuade the few remaining tamoxifen and progestin aficionados to finally switch to using aromatase inhibitors as upfront therapy. However, tamoxifen and other hormonal therapy agents remain important therapeutic options either as part of a sequential hormonal treatment strategy or as first-line therapy for breast cancer that has relapsed while the patient is taking an aromatase inhibitor as adjuvant therapy. C. X. Ma, MD, PhD M. J. Ellis, MB, PhD
312 312
®
Breast Diseases: A Year Book Quarterly Vol 18 No 3 2007
Reference 1. Wong ZW, Ellis MJ: First-line endocrine treatment of breast cancer: Aromatase inhibitor or antioestrogen? Br J Cancer 90:20-25, 2004.
A Prospective, Longitudinal Study of the Functional Status and Quality of Life of Older Patients With Breast Cancer Receiving Adjuvant Chemotherapy Hurria A, Hurria A, Zuckerman E, et al J Am Geriatr Soc 54:1119-1124, 2006 Clinicians are often faced with difficult decisions regarding recommendations for adjuvant chemotherapy in elderly women with breast cancer. In light of medical comorbidities, does the potential for increased toxicity outweigh the disease-free and overall survival benefits? Hurria and colleagues followed elderly patients receiving adjuvant chemotherapy for breast cancer and specifically examined this risk-benefit ratio. Older patients with newly diagnosed early breast cancer treated with standard adjuvant chemotherapy regimens were functionally assessed utilizing accepted geriatric tools of functional assessments. The median age of participants on this study was described as “younger elderly” at age 68 years, but the range of ages (65-84 years) is typical of older patients seen in busy oncology practices. Therefore, information gleaned from this study is useful for treatment planning. Albeit because the authors were located at a well-known tertiary referral center, the patients included in this clinical trial could be somewhat self-selected in that they have the support and ability to seek out specialized care. One would expect that such patients would possess a higher functional status. Therefore, an inherent selection bias may exist. Nevertheless, it is still very gratifying that despite approximately half of the patients experiencing the expected chemotherapy-associated toxicities, there was no significant decline in longitudinal quality of life. This population did not seem to lose functional status. This study is important because it highlights the possibility of bias that we as physicians display when faced with treating an older patient in the same manner as we would approach a younger patient (age less than 50 years). The idea of clinician bias is further supported by the fact that an Intergroup Trial, CALGB 49907, an adjuvant study randomizing patients aged 65 years or greater to treatment with either doxorubicin and cyclophosphamide or cyclophosphamide, methotrexate, and 5-fluorouracil versus oral capecitabine, has not been able to meet accrual for the past several years. This is despite the fact that the majority of patients with breast cancer eligible for chemotherapy are older and that data suggest that, if offered, older women are likely to accept adjuvant chemotherapy recommendations and enroll in adjuvant therapeutic clinical trials.1,2 Because of advances in the standard of living as well as the successes of modern and preventative medicine, the older population is increasing and will continue to enjoy good health and functionality. Therefore, looking forward, potentially larger numbers of patients can be expected to be included in the category of “the elderly” and may be candidates for curative, definitive adjuvant therapy. Although the numbers of patients in this prospectively acquired