- Email: [email protected]
Linking contralateral breast cancer with genetics
Radiotherapy and Oncology 86 (2008) 139–141 www.thegreenjournal.com
Editorial
Linking contralateral breast cancer with genetics Dimitrios H. Roukos* Department of Surgery, Ioannina University School of Medicine, Ioannina, Greece
Breast cancer is the most common malignancy in females with more than 1,150,000 new cases diagnosed each year worldwide. Incidence of the disease is now declining in the USA due to a decline in the use of hormone replacement therapy [1]. Advances in local and systemic treatment strategies have improved survival rates [1]. The large number of long-term survivors has revealed the problem of contralateral breast cancer (CBC). Descriptive studies have shown the efficiency of contralateral prophylactic mastectomy (CPM) in preventing CBC [2]. These data and the fear of patients for a new breast cancer in the unaffected breast probably explain the dramatic increase of a more aggressive surgery such as CPM in the USA [3]. Does radiotherapy with internal mammary field contributes to increased risk of CBC? Does CPM benefits patients or it represents an overtreatment with harms for patients, society and public health? Can high-risk patients be identified before clinical occurrence for risk stratification-based guided treatment to prevent CBC? Yaday and colleagues in a recent issue of the Journal discussed later [4] address these questions. Current standards for the treatment of early breast cancer include surgery with or without radiotherapy (RT) for local control and adjuvant systemic treatment for preventing distant recurrence. Surgery includes breast-conserving surgery (BCS), unilateral mastectomy, CPM and sentinel node biopsy for avoiding axilla lymphadenectomy. There are criteria for choosing extent of surgery considering risk of local recurrence, cosmetic results and quality of life, but decisions in several cases are complex [5–7]. In 2007, the International Panel Consensus on the primary therapy of early breast cancer was published [5]. Radiation therapy has certain indications. Even following BCS, RT would be avoided in elderly patients who would receive endocrine therapy. In general, post-mastectomy RT would be restricted to patients with 4 or more involved axillary lymph nodes while it is unclear whether the benefits of RT overcome the harms in patients with 1–3 positive nodes. Radiation therapy is not recommended for patients with node-negative disease and T1–T2 tumors. Post-mastectomy irradiation volume should include chest wall and supraclavicular fossa for those with axillary nodes involved. In general axillary radiation should be avoided if proper axillary clearance has been performed [5]. Does local control impacts overall survival? Previous single randomized controlled trials (RCTs) showed an increased
risk of local recurrence without any increase in mortality. But a recent landmark meta-analysis of 78 RCTs [6] alters this hypothesis. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) report analyzed data from 42,000 patients with breast cancer and examined more extensive versus less extensive surgery, radiation therapy versus no radiation therapy, and extensive surgery versus radiation therapy. Improved local control at 5 years resulted in a highly statistically significant improvement in both breast cancer survival and overall survival at 15 years. Although local control is important for survival a generalization should be avoided. For example, aggressive surgery and/or RT should be restricted to patients at high-risk of local recurrence because of complications and side effects. More robust predictors of local recurrence are needed to guide an appropriate treatment [8]. What is the magnitude of CBC risk, which factors linked to this occurrence and what is the role of RT? Specific clinico-pathologic features and genetic factors are associated with an increased risk of developing CBC. These include young patient age, a family history of breast cancer, lobular type histology, multicentric cancer, and previous chest radiation. The overall annual incidence of CBC after unilateral breast cancer diagnosis is about 0.5–0.75%; the highest risk of 3% annually or 30% to 39% at 10 years has been reported for patients who are carriers of mutations in BRCA1 or BRCA2 (BRCA1/2 or BRCA) genes [9,10]. Highly significant difference between BRCA carriers and noncarriers have been reported [10]. In contrast to other conventional risk factors, strong experimental evidence is available only for BRCA carriers: inherited mutations of BRCA cancer susceptibility genes involved in double-strand DNA break repair lead to breast cancer [11]. Unsurprisingly therefore, tumors arisen in the unaffected breast due to BRCA-deficient cells [12]. In this issue (pages xxx–xxx) of the Journal Yaday et al. [4] provide clinical data how to identify high-risk patients for CBC development. The authors analyzed data from 1084 breast cancer patients to evaluate incidence of and risk factors for CBC. Most women underwent mastectomy (87%) and postoperative RT (88%). The authors followed Manchester shorter fractionation schedule 35 Gy to chest wall and 40 Gy to axilla and supraclavicular region in axillary lymph node-positive patients and some node-negative patients. In a small fraction of patients (13%) tangent plus
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.01.013
140
Editorial
internal mammary RT was given. Half of patients received chemotherapy either CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or FAC (5-fluorouracil, adriamycin, cyclophosphamide) and 68% hormonal therapy (20 mg daily tamoxifen for 5 years) irrespective of ER/PR status. After a median follow-up of 12 years, the 10 and 20 year actuarial rate of CBC was 5.6% and 11.3%, respectively. Treatment strategy for breast cancer in the Yaday et al. report was appropriate according to the guidelines of the time period of the study (1985–1995). Thus, the results reported are consistent with the literature; overall incidence of CBC was low (4%) and RT had no impact on a subsequent risk of CBC. In the subsets of patients aged <45 years, particularly when they received an internal mammary field RT, the risk of CBC was significantly increased. How useful can these data be when treatment strategy has been changed? Indeed, local and adjuvant systemic treatment have been altered. In the Yaday et al. report tamoxifen was given irrespective of ER/PR status. But currently, hormonal therapy is recommended only for ER and/or PR-positive disease; usually a switch from tamoxifen to an aromatase inhibitor ‘‘AI’’ after 2–3 years of tamoxifen. This more effective therapy may further decrease the risk of CBC. New data are required from studies which will include ER/PR assessment for both primary tumor and CBC to assess relationships. Furthermore, in the absence of long-term follow-up results the impact of targeted therapy with trastuzumab to HER2-positive disease and modern empirical cytotoxic regimens on CBC incidence is unknown. Another limitation of the study [4] is the small number of patients who developed CBC after therapy: only 43 patients. Thus, subgroup analysis with Kaplan–Meier method for such a small number of events (contralateral cancers) may be associated with biases. Breast cancer is a heterogeneous disease with several molecular and genetic groups that may require a different treatment to achieve the highest clinical response. Currently, patients are treated according to HER2, ER/PR status and ‘‘classic’’ conventional clinicopathologic features (age, nodal status, tumor size, histological grade) [5]. Microarrays-based global gene-expression profiling studies of primary tumor have revealed several molecular subtypes with different pathological, clinical and prognostic characteristics as well as response to specific therapies: luminal A and B (ER-positive tumors), HER2-like (HER2-positive disease) and basal-like tumors (triple negative HER2/ER/PRnegative cancer) [13]. Although aggressive surgery followed by radiotherapy prevent local and nodal failures and risk of CBC, they are associated with complications, toxicity and adverse effects in QOL [14]. It is clearly not a progress to come back again in the aggressive treatments of the past. Safe, patient-friendly, less aggressive therapies with better QOL are now available. Then, how can we prevent CBC? In the post-genomic era, personalized approaches using genetic and molecular tools find wide clinical implications [15]. BRCA genetic testing is now increasingly incorporated into the pretreatment diagnostic workup of patients with breast cancer and a family history [16]. There is scientific evidence from both basic science and epidemiological studies that the subset of patients with inherited BRCA mutations is truly at high-risk of developing CBC after
unilateral breast cancer therapy [10–12]. Whether young patients and those with a family history who are tested negative for BRCA mutations (nonBRCA carriers) are also at increased risk of CBC is unknown. New studies are required to define this risk. Personalized medicine is the major goal but also the greatest challenge for the future. Identifying and validating class II and III prognostic and predictive biomarkers, respectively, will maximize the benefits for patients, public health and society [17]. But there are multiple challenges and hurdles to be overcome to reach an update optimum individualized therapy. The overall risk of CBC should not be overestimated; but high-risk individuals identified by genetic testing require careful consideration. In the future, cancer genome and functional studies and the current availability of high-throughput analyses techniques as genomewide association studies on the basis of microarray-chips with one million single-nucleotide-polymorphisms (SNPs), RNA interference and genomics promise to provide faster more accurate predictors of response to specific therapies [18,19]. Modern radiation therapy techniques allow reduction of normal tissue damage to heart and lungs. Ongoing research evaluates whether in carefully selected patients RT would be limited to the part of the breast closest to the site of the excised tumor (accelerated partial external or intraoperative irradiation). * Dimitrios H. Roukos, Department of Surgery, Ioannina University School of Medicine, Surgical Oncology Research Unit, 451 10 Ioannina, Greece. E-mail address: [email protected] Received 6 January 2008; accepted 14 January 2008; Available online 30 January 2008
References [1] Gralow J, Ozols RF, Bajorin DF, et al. Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening a report from the american society of clinical oncology. J Clin Oncol 2008;26:313–25. [2] Herrinton LJ, Barlow WE, Yu O, et al. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a cancer research network project. J Clin Oncol 2005;23:4275–86. [3] Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol 2007;25:5203–9. [4] Yadav BS, Sharma SC, Patel FD, Ghoshal S, Kapoor RK. Second primary in the contralateral breast after treatment of breast cancer. Radiother Oncol. 2007 Oct 23; [Epub ahead of print]. [5] Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18:1133–44. [6] Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. [7] Roukos DH, Kappas AM, Agnantis NJ. Perspectives and risks of breast-conservation therapy for breast cancer. Ann Surg Oncol 2003;10:718–21. [8] Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in breast cancer. N Engl J Med 2007;356:2399–405. [9] Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol 2005;23:1656–63.
D.H. Roukos / Radiotherapy and Oncology 86 (2008) 139–141 [10] Pierce LJ et al. Ten-year multi-institutional results of breastconserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 2006;24:2437–43. [11] Farmer H et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:917–21. [12] Roukos DH, Briasoulis E. Individualized preventive and therapeutic management of hereditary breast ovarian cancer. Nat Clin Pract Oncol 2007;4:578–90. [13] Sotiriou C, Piccart MJ. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 2007;7:545–53. [14] Fatouros M, Baltoyiannis G, Roukos DH. The predominant role of surgery in the prevention and new trends in the surgical treatment of hereditary breast ovarian cancer. Ann Surg Oncol 2008;15:21–33.
141
[15] Roukos DH, Murray S, Briasoulis E. Molecular genetic tools shape a roadmap towards a more accurate prognostic prediction and personalized management of cancer. Cancer Biol Ther 2007;6:308–12. [16] Roukos DH. Prognosis of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007;357:1555–6, author reply 1556. [17] Roukos DH. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 2008;358:197. [18] Wood LD, Parsons DW, Jones S. The genomic landscapes of human breast and colorectal cancers. Science 2007;318:1108–13. [19] Roukos DH. Innovative genomic-based model for personalized treatment of gastric cancer: integrating current standards and new technologies. Expert Rev Mol Diagn 2008;8:29–39.
Editorial
Linking contralateral breast cancer with genetics Dimitrios H. Roukos* Department of Surgery, Ioannina University School of Medicine, Ioannina, Greece
Breast cancer is the most common malignancy in females with more than 1,150,000 new cases diagnosed each year worldwide. Incidence of the disease is now declining in the USA due to a decline in the use of hormone replacement therapy [1]. Advances in local and systemic treatment strategies have improved survival rates [1]. The large number of long-term survivors has revealed the problem of contralateral breast cancer (CBC). Descriptive studies have shown the efficiency of contralateral prophylactic mastectomy (CPM) in preventing CBC [2]. These data and the fear of patients for a new breast cancer in the unaffected breast probably explain the dramatic increase of a more aggressive surgery such as CPM in the USA [3]. Does radiotherapy with internal mammary field contributes to increased risk of CBC? Does CPM benefits patients or it represents an overtreatment with harms for patients, society and public health? Can high-risk patients be identified before clinical occurrence for risk stratification-based guided treatment to prevent CBC? Yaday and colleagues in a recent issue of the Journal discussed later [4] address these questions. Current standards for the treatment of early breast cancer include surgery with or without radiotherapy (RT) for local control and adjuvant systemic treatment for preventing distant recurrence. Surgery includes breast-conserving surgery (BCS), unilateral mastectomy, CPM and sentinel node biopsy for avoiding axilla lymphadenectomy. There are criteria for choosing extent of surgery considering risk of local recurrence, cosmetic results and quality of life, but decisions in several cases are complex [5–7]. In 2007, the International Panel Consensus on the primary therapy of early breast cancer was published [5]. Radiation therapy has certain indications. Even following BCS, RT would be avoided in elderly patients who would receive endocrine therapy. In general, post-mastectomy RT would be restricted to patients with 4 or more involved axillary lymph nodes while it is unclear whether the benefits of RT overcome the harms in patients with 1–3 positive nodes. Radiation therapy is not recommended for patients with node-negative disease and T1–T2 tumors. Post-mastectomy irradiation volume should include chest wall and supraclavicular fossa for those with axillary nodes involved. In general axillary radiation should be avoided if proper axillary clearance has been performed [5]. Does local control impacts overall survival? Previous single randomized controlled trials (RCTs) showed an increased
risk of local recurrence without any increase in mortality. But a recent landmark meta-analysis of 78 RCTs [6] alters this hypothesis. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) report analyzed data from 42,000 patients with breast cancer and examined more extensive versus less extensive surgery, radiation therapy versus no radiation therapy, and extensive surgery versus radiation therapy. Improved local control at 5 years resulted in a highly statistically significant improvement in both breast cancer survival and overall survival at 15 years. Although local control is important for survival a generalization should be avoided. For example, aggressive surgery and/or RT should be restricted to patients at high-risk of local recurrence because of complications and side effects. More robust predictors of local recurrence are needed to guide an appropriate treatment [8]. What is the magnitude of CBC risk, which factors linked to this occurrence and what is the role of RT? Specific clinico-pathologic features and genetic factors are associated with an increased risk of developing CBC. These include young patient age, a family history of breast cancer, lobular type histology, multicentric cancer, and previous chest radiation. The overall annual incidence of CBC after unilateral breast cancer diagnosis is about 0.5–0.75%; the highest risk of 3% annually or 30% to 39% at 10 years has been reported for patients who are carriers of mutations in BRCA1 or BRCA2 (BRCA1/2 or BRCA) genes [9,10]. Highly significant difference between BRCA carriers and noncarriers have been reported [10]. In contrast to other conventional risk factors, strong experimental evidence is available only for BRCA carriers: inherited mutations of BRCA cancer susceptibility genes involved in double-strand DNA break repair lead to breast cancer [11]. Unsurprisingly therefore, tumors arisen in the unaffected breast due to BRCA-deficient cells [12]. In this issue (pages xxx–xxx) of the Journal Yaday et al. [4] provide clinical data how to identify high-risk patients for CBC development. The authors analyzed data from 1084 breast cancer patients to evaluate incidence of and risk factors for CBC. Most women underwent mastectomy (87%) and postoperative RT (88%). The authors followed Manchester shorter fractionation schedule 35 Gy to chest wall and 40 Gy to axilla and supraclavicular region in axillary lymph node-positive patients and some node-negative patients. In a small fraction of patients (13%) tangent plus
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.01.013
140
Editorial
internal mammary RT was given. Half of patients received chemotherapy either CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or FAC (5-fluorouracil, adriamycin, cyclophosphamide) and 68% hormonal therapy (20 mg daily tamoxifen for 5 years) irrespective of ER/PR status. After a median follow-up of 12 years, the 10 and 20 year actuarial rate of CBC was 5.6% and 11.3%, respectively. Treatment strategy for breast cancer in the Yaday et al. report was appropriate according to the guidelines of the time period of the study (1985–1995). Thus, the results reported are consistent with the literature; overall incidence of CBC was low (4%) and RT had no impact on a subsequent risk of CBC. In the subsets of patients aged <45 years, particularly when they received an internal mammary field RT, the risk of CBC was significantly increased. How useful can these data be when treatment strategy has been changed? Indeed, local and adjuvant systemic treatment have been altered. In the Yaday et al. report tamoxifen was given irrespective of ER/PR status. But currently, hormonal therapy is recommended only for ER and/or PR-positive disease; usually a switch from tamoxifen to an aromatase inhibitor ‘‘AI’’ after 2–3 years of tamoxifen. This more effective therapy may further decrease the risk of CBC. New data are required from studies which will include ER/PR assessment for both primary tumor and CBC to assess relationships. Furthermore, in the absence of long-term follow-up results the impact of targeted therapy with trastuzumab to HER2-positive disease and modern empirical cytotoxic regimens on CBC incidence is unknown. Another limitation of the study [4] is the small number of patients who developed CBC after therapy: only 43 patients. Thus, subgroup analysis with Kaplan–Meier method for such a small number of events (contralateral cancers) may be associated with biases. Breast cancer is a heterogeneous disease with several molecular and genetic groups that may require a different treatment to achieve the highest clinical response. Currently, patients are treated according to HER2, ER/PR status and ‘‘classic’’ conventional clinicopathologic features (age, nodal status, tumor size, histological grade) [5]. Microarrays-based global gene-expression profiling studies of primary tumor have revealed several molecular subtypes with different pathological, clinical and prognostic characteristics as well as response to specific therapies: luminal A and B (ER-positive tumors), HER2-like (HER2-positive disease) and basal-like tumors (triple negative HER2/ER/PRnegative cancer) [13]. Although aggressive surgery followed by radiotherapy prevent local and nodal failures and risk of CBC, they are associated with complications, toxicity and adverse effects in QOL [14]. It is clearly not a progress to come back again in the aggressive treatments of the past. Safe, patient-friendly, less aggressive therapies with better QOL are now available. Then, how can we prevent CBC? In the post-genomic era, personalized approaches using genetic and molecular tools find wide clinical implications [15]. BRCA genetic testing is now increasingly incorporated into the pretreatment diagnostic workup of patients with breast cancer and a family history [16]. There is scientific evidence from both basic science and epidemiological studies that the subset of patients with inherited BRCA mutations is truly at high-risk of developing CBC after
unilateral breast cancer therapy [10–12]. Whether young patients and those with a family history who are tested negative for BRCA mutations (nonBRCA carriers) are also at increased risk of CBC is unknown. New studies are required to define this risk. Personalized medicine is the major goal but also the greatest challenge for the future. Identifying and validating class II and III prognostic and predictive biomarkers, respectively, will maximize the benefits for patients, public health and society [17]. But there are multiple challenges and hurdles to be overcome to reach an update optimum individualized therapy. The overall risk of CBC should not be overestimated; but high-risk individuals identified by genetic testing require careful consideration. In the future, cancer genome and functional studies and the current availability of high-throughput analyses techniques as genomewide association studies on the basis of microarray-chips with one million single-nucleotide-polymorphisms (SNPs), RNA interference and genomics promise to provide faster more accurate predictors of response to specific therapies [18,19]. Modern radiation therapy techniques allow reduction of normal tissue damage to heart and lungs. Ongoing research evaluates whether in carefully selected patients RT would be limited to the part of the breast closest to the site of the excised tumor (accelerated partial external or intraoperative irradiation). * Dimitrios H. Roukos, Department of Surgery, Ioannina University School of Medicine, Surgical Oncology Research Unit, 451 10 Ioannina, Greece. E-mail address: [email protected] Received 6 January 2008; accepted 14 January 2008; Available online 30 January 2008
References [1] Gralow J, Ozols RF, Bajorin DF, et al. Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening a report from the american society of clinical oncology. J Clin Oncol 2008;26:313–25. [2] Herrinton LJ, Barlow WE, Yu O, et al. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a cancer research network project. J Clin Oncol 2005;23:4275–86. [3] Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol 2007;25:5203–9. [4] Yadav BS, Sharma SC, Patel FD, Ghoshal S, Kapoor RK. Second primary in the contralateral breast after treatment of breast cancer. Radiother Oncol. 2007 Oct 23; [Epub ahead of print]. [5] Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18:1133–44. [6] Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. [7] Roukos DH, Kappas AM, Agnantis NJ. Perspectives and risks of breast-conservation therapy for breast cancer. Ann Surg Oncol 2003;10:718–21. [8] Punglia RS, Morrow M, Winer EP, Harris JR. Local therapy and survival in breast cancer. N Engl J Med 2007;356:2399–405. [9] Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol 2005;23:1656–63.
D.H. Roukos / Radiotherapy and Oncology 86 (2008) 139–141 [10] Pierce LJ et al. Ten-year multi-institutional results of breastconserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 2006;24:2437–43. [11] Farmer H et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:917–21. [12] Roukos DH, Briasoulis E. Individualized preventive and therapeutic management of hereditary breast ovarian cancer. Nat Clin Pract Oncol 2007;4:578–90. [13] Sotiriou C, Piccart MJ. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 2007;7:545–53. [14] Fatouros M, Baltoyiannis G, Roukos DH. The predominant role of surgery in the prevention and new trends in the surgical treatment of hereditary breast ovarian cancer. Ann Surg Oncol 2008;15:21–33.
141
[15] Roukos DH, Murray S, Briasoulis E. Molecular genetic tools shape a roadmap towards a more accurate prognostic prediction and personalized management of cancer. Cancer Biol Ther 2007;6:308–12. [16] Roukos DH. Prognosis of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007;357:1555–6, author reply 1556. [17] Roukos DH. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 2008;358:197. [18] Wood LD, Parsons DW, Jones S. The genomic landscapes of human breast and colorectal cancers. Science 2007;318:1108–13. [19] Roukos DH. Innovative genomic-based model for personalized treatment of gastric cancer: integrating current standards and new technologies. Expert Rev Mol Diagn 2008;8:29–39.