REVIEWS Management of locally advanced breast cancer—perspectives and future directions Konstantinos Tryfonidis, Elzbieta Senkus, Maria J. Cardoso and Fatima Cardoso Abstract | Locally advanced breast cancer (LABC) constitutes a heterogeneous entity that includes advancedstage primary tumours, cancers with extensive nodal involvement and inflammatory breast carcinomas. Although the definition of LABC can be broadened to include some large operable breast tumours, we use this term to strictly refer to inoperable cancers that are included in the above-mentioned categories. The prognosis of such tumours is often unfavourable; despite aggressive treatment, many patients eventually develop distant metastases and die from the disease. Advances in systemic therapy, including radiation treatment, surgical techniques and the development of new targeted agents have significantly improved clinical outcomes for patients with this disease. Notwithstanding these advances, LABC remains an important clinical problem, particularly in developing countries and those without widely adapted breast cancer awareness programmes. The optimal management of LABC requires a multidisciplinary approach, a well-coordinated treatment schedule and close cooperation between medical, surgical and radiation oncologists. In this Review, we discuss the current state of the art and possible future treatment strategies for patients with LABC. Tryfonidis, K. et al. Nat. Rev. Clin. Oncol. 12, 147–162 (2015); published online 10 February 2015; corrected online 14 April 2015; doi:10.1038/nrclinonc.2015.13
Introduction
European Organisation for Research and Treatment of Cancer (EORTC) Headquarters & Breast Cancer Group, Avenue Mounier 83/11, 1200 Brussels, Belgium (K.T.). Department of Oncology and Radiotherapy, Medical University of Gdansk, Ul Debinki 7, 80211 Gdansk, Poland (E.S.). Breast Unit, Champalimaud Clinical Centre, Avenida De Brasília s/n, 1400‑038 Lisbon, Portugal (M.J.C., F.C.). Correspondence to: F.C. fatimacardoso@fundacao champalimaud.pt
Locally advanced inoperable breast cancer (LABC) constitutes a major clinical challenge, because the vast majority of patients with LABC will experience disease relapse and eventually die, despite aggressive multimodality treatment.1 LABC usually encompasses stage III disease, defined as T0–T3 primary tumours with clinically detectable axillary (matted or fixed), ipsilateral infraclavicular, supraclavicular or internal mammary lymph nodes (N2 or N3 disease) or tumour extension to the chest wall or skin (T4) regardless of nodal status.2 In some cases the definition of LABC is broadened to include patients with clinical stage IIB disease, such as primary tumour ≥5 cm and no nodal involvement (T3 N0). However, most experts consider patients with stage IIB–IIIA (T3 N0–1) as ‘large operable’ breast cancers, in contrast to truly inoperable cases with inflammatory and/or extensive skin involvement, fixed or very bulky axillary nodal disease and/or supraclavicular or internal mammary nodal involvement.3 For the purpose of this Review, our definition of LABC is limited to the latter. Inflammatory breast carcinoma (IBC) is a rare, aggressive and specific entity of LABC. At clinical diagnosis, IBC is defined as erythema and dermal oedema (usually Competing interests E.S. is an advisory board member for Roche, has received travel support from Novartis and belongs to the speakers’ bureau for AstraZeneca, GSK and Roche. F.C. has received Consultant/ honouraria and is an advisory board member for Astellas, Astra‑Zeneca, Celgene, Daiichi-Sankyo, Eisai, Genentech/Roche, GE Oncology, GlaxoSmithKline, Merck-Sharp, Merus, Novartis, Pfizer, and Sanofi. K.T. and M.J.C. have no competing interests.
called peau d’orange) occurring over a substantial breast area. Clinical diagnosis is usually accompanied by pathological findings of tumour emboli in dermal lymphatics, although this finding is not necessary or sufficient (if clinical symptoms are lacking) to confirm the diagnosis of IBC.4,5 The term ‘secondary inflammatory breast carcinoma’ is used to describe skin changes mimicking primary IBC, such as those resulting from non-inflammatory LABC or breast cancer recurrence in a previously treated breast and/or chest wall.4,5 Patients with LABC must be managed with combined therapy employing systemic and locoregional modalities, and require a well-coordinated treatment schedule and close cooperation between medical, surgical and radiation oncologists.6 This Review describes the current treatment options for the management of patients with LABC. In this context, IBC is discussed separately from other types of LABC, owing to its distinct clinical characteristics and prognosis.
Epidemiology, prognosis and risk factors
Breast cancer is the most frequently diagnosed malignancy and the second most common cause of cancerrelated death in women worldwide.7 According to the Surveillance, Epidemiology and End Results (SEER) data, 5‑year survival rates in patients presenting with stages IIIA and IIIB breast cancer are 52% and 48% respectively, and the median survival for stage III is 4.9 years.4,8 Data from the National Cancer Database and the CONCORD high-resolution study in Europe indicate that approximately 8.5% of American and 4% of
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 12 | MARCH 2015 | 147 © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ The definition of locally advanced breast cancer (LABC) can be broadened to include large operable tumours, however, we commonly use this term to refer to inoperable cancers ■■ The management of LABC constitutes an important clinical problem, particularly in developing countries and those without widely adapted awareness programmes ■■ The optimal management of LABC requires a multidisciplinary approach and collaboration between medical, surgical and radiation oncologists ■■ Few data exist on LABC systemic treatment; the majority of data are from studies including both large-operable and locally advanced inoperable tumours—posing many challenges in the management of LABC ■■ Several new molecularly targeted agents are under clinical investigation aiming to improve the clinical outcome of patients with LABC ■■ The negative results of the ALTTO trial after promising data from NeoALTTO advocate a reassessment of pathological complete response as a suitable surrogate marker for long-term outcome in breast cancer
European patients with breast cancer present with LABC.9 This percentage decreases significantly in populations undergoing regular screening programmes; however, it can reach as high as 60% in low-resources countries.10–12 Primary IBC is a relatively rare disorder and accounts for approximately 1–5% of invasive breast cancer 13,14 and 8.5% of LABC.3,15 In the MD Anderson series of 752 patients with stage III breast cancer, 24 (3%) had IBC.16 The long–term prognosis of IBC remains poor. In the SEER data, 2‑year breast-cancer-specific survival (BCSS) in IBC was significantly worse than in noninflammatory LABC (84% versus 91%, HR 1.43 [95% CI, 1.097–1.854]).17 However, owing to advances in multi disciplinary management of this disease, the 20-year BCSS for patients with IBC treated in the period between 1975 and 1995 has increased from 9% to 20%.18 In a SEER-based study of 7,679 patients with IBC diagnosed between 1990 and 2010 a significant and stepwise survival improvement was seen among women with stage III IBC, regardless of race, age or hormone receptor status. This result suggests that new strategies developed in the context of non-IBC probably had a positive impact on IBC patients.19 Several risk factors have been associated with the development of IBC: race (with higher incidence among black and Hispanic populations, and black women being diagnosed at a younger age); obesity; young age at first delivery; rural residence and longer cumulative duration of breastfeeding. Interestingly, IBC develops at a younger age compared to other forms of LABC and early stage breast cancer (mean age of 58.8 years, 66.2 years and 61.7 years, respectively).20–22
Pathobiology and prognostic factors
The histopathology of LABC, with its prevailing infiltrating ductal and lobular carcinomas is relatively similar to that of early stage disease. ‘Favourable’ histologies, such as tubular or medullary carcinomas, rarely present at an advanced stage unless they have been growing over a long period of time (neglected cases) and are more often encountered with advanced age.23,24 The prognostic role of hormone receptor status is similar to that in early stage disease, and positivity is 148 | MARCH 2015 | VOLUME 12
associated with better outcome.25 Compared to nonIBC, IBC is more frequently oestrogen receptor (ER) and progesterone receptor (PgR) negative. 26,27 ER expression remains an important prognostic factor for IBC; in the 1988–2000 SEER dataset, patients with ER‑positive IBC had longer median survival compared to patients with ER‑negative disease (4 years versus 2 years, P = 0.0001).22,26–28 Several specific molecular and biological features of IBC, such as its prominent angiogenic properties, reflect its aggressive behaviour and high metastatic potential.29 Increased mRNA expression of several angiogenic markers, including VEGF and its receptor VEGFR, have been demonstrated in IBC tissue samples. This angio invasive nature seems to be intrinsic to IBC and might constitute a rationale for specific treatment strategies.29,30 Interestingly, apart from high expression of VEGF‑D (a ligand of VEGFR‑3) in IBC, cell-line studies have also demonstrated increased levels of several other cytokines, such as bFGF, FGF‑2, IL‑6 and IL‑8 in addition to the most common ones, including IFN‑γ, IL‑1 and IL‑12.31–33 Primary IBC tumours are usually of high-grade ductal type, with atypical mitotic figures and high micro vessel density. A classic finding on the biopsy of affected skin is invasion of dermal lymphatics by the tumour cells. These tumour emboli are the main local signs of the disease and are thought to be responsible for its metastatic potential.34, 35 Two genes, RhoC GTPase and WISP3 (also known as lost in IBC, LIBC) were found to be altered in 91% of IBC cases.36,37 Overexpression of RhoC GTPase, whose gene product is involved in cytoskeleton reorganization, correlates with tumour progression and constitutes an important contributor to the IBC metastatic phenotype.36 The gene WISP3 encodes for an insulin-like growth factor binding protein-related protein (IGFBPrP). Downregulation or loss of IGFBPrP‑1 is associated with progression of IBC, whereas transfection of WISP3 into an inflammatory breast cancer cell line inhibited tumour growth, invasiveness and angiogenic potential, thus acting as a tumour suppressor gene.36,37 Several studies have also shown that IBC is often characterized by the high expression of genes associated with increased metabo lism and cell turnover, although these observations were only reported in a small number of cases and, therefore, no clear conclusions can be drawn. 38,39 Nonetheless, most of these studies confirm the genetic heterogeneity of IBC and the consistent biological differences between IBC and cancers of a non-IBC nature.28,38,39 A PAM50 analysis was conducted among 137 IBC (and 252 non-IBC cases), identifying all four intrinsic breast cancer subtypes; specifically, the luminal A subtype was less frequent than in non-IBC (19% versus 42%, P
Introduction
European Organisation for Research and Treatment of Cancer (EORTC) Headquarters & Breast Cancer Group, Avenue Mounier 83/11, 1200 Brussels, Belgium (K.T.). Department of Oncology and Radiotherapy, Medical University of Gdansk, Ul Debinki 7, 80211 Gdansk, Poland (E.S.). Breast Unit, Champalimaud Clinical Centre, Avenida De Brasília s/n, 1400‑038 Lisbon, Portugal (M.J.C., F.C.). Correspondence to: F.C. fatimacardoso@fundacao champalimaud.pt
Locally advanced inoperable breast cancer (LABC) constitutes a major clinical challenge, because the vast majority of patients with LABC will experience disease relapse and eventually die, despite aggressive multimodality treatment.1 LABC usually encompasses stage III disease, defined as T0–T3 primary tumours with clinically detectable axillary (matted or fixed), ipsilateral infraclavicular, supraclavicular or internal mammary lymph nodes (N2 or N3 disease) or tumour extension to the chest wall or skin (T4) regardless of nodal status.2 In some cases the definition of LABC is broadened to include patients with clinical stage IIB disease, such as primary tumour ≥5 cm and no nodal involvement (T3 N0). However, most experts consider patients with stage IIB–IIIA (T3 N0–1) as ‘large operable’ breast cancers, in contrast to truly inoperable cases with inflammatory and/or extensive skin involvement, fixed or very bulky axillary nodal disease and/or supraclavicular or internal mammary nodal involvement.3 For the purpose of this Review, our definition of LABC is limited to the latter. Inflammatory breast carcinoma (IBC) is a rare, aggressive and specific entity of LABC. At clinical diagnosis, IBC is defined as erythema and dermal oedema (usually Competing interests E.S. is an advisory board member for Roche, has received travel support from Novartis and belongs to the speakers’ bureau for AstraZeneca, GSK and Roche. F.C. has received Consultant/ honouraria and is an advisory board member for Astellas, Astra‑Zeneca, Celgene, Daiichi-Sankyo, Eisai, Genentech/Roche, GE Oncology, GlaxoSmithKline, Merck-Sharp, Merus, Novartis, Pfizer, and Sanofi. K.T. and M.J.C. have no competing interests.
called peau d’orange) occurring over a substantial breast area. Clinical diagnosis is usually accompanied by pathological findings of tumour emboli in dermal lymphatics, although this finding is not necessary or sufficient (if clinical symptoms are lacking) to confirm the diagnosis of IBC.4,5 The term ‘secondary inflammatory breast carcinoma’ is used to describe skin changes mimicking primary IBC, such as those resulting from non-inflammatory LABC or breast cancer recurrence in a previously treated breast and/or chest wall.4,5 Patients with LABC must be managed with combined therapy employing systemic and locoregional modalities, and require a well-coordinated treatment schedule and close cooperation between medical, surgical and radiation oncologists.6 This Review describes the current treatment options for the management of patients with LABC. In this context, IBC is discussed separately from other types of LABC, owing to its distinct clinical characteristics and prognosis.
Epidemiology, prognosis and risk factors
Breast cancer is the most frequently diagnosed malignancy and the second most common cause of cancerrelated death in women worldwide.7 According to the Surveillance, Epidemiology and End Results (SEER) data, 5‑year survival rates in patients presenting with stages IIIA and IIIB breast cancer are 52% and 48% respectively, and the median survival for stage III is 4.9 years.4,8 Data from the National Cancer Database and the CONCORD high-resolution study in Europe indicate that approximately 8.5% of American and 4% of
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 12 | MARCH 2015 | 147 © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ The definition of locally advanced breast cancer (LABC) can be broadened to include large operable tumours, however, we commonly use this term to refer to inoperable cancers ■■ The management of LABC constitutes an important clinical problem, particularly in developing countries and those without widely adapted awareness programmes ■■ The optimal management of LABC requires a multidisciplinary approach and collaboration between medical, surgical and radiation oncologists ■■ Few data exist on LABC systemic treatment; the majority of data are from studies including both large-operable and locally advanced inoperable tumours—posing many challenges in the management of LABC ■■ Several new molecularly targeted agents are under clinical investigation aiming to improve the clinical outcome of patients with LABC ■■ The negative results of the ALTTO trial after promising data from NeoALTTO advocate a reassessment of pathological complete response as a suitable surrogate marker for long-term outcome in breast cancer
European patients with breast cancer present with LABC.9 This percentage decreases significantly in populations undergoing regular screening programmes; however, it can reach as high as 60% in low-resources countries.10–12 Primary IBC is a relatively rare disorder and accounts for approximately 1–5% of invasive breast cancer 13,14 and 8.5% of LABC.3,15 In the MD Anderson series of 752 patients with stage III breast cancer, 24 (3%) had IBC.16 The long–term prognosis of IBC remains poor. In the SEER data, 2‑year breast-cancer-specific survival (BCSS) in IBC was significantly worse than in noninflammatory LABC (84% versus 91%, HR 1.43 [95% CI, 1.097–1.854]).17 However, owing to advances in multi disciplinary management of this disease, the 20-year BCSS for patients with IBC treated in the period between 1975 and 1995 has increased from 9% to 20%.18 In a SEER-based study of 7,679 patients with IBC diagnosed between 1990 and 2010 a significant and stepwise survival improvement was seen among women with stage III IBC, regardless of race, age or hormone receptor status. This result suggests that new strategies developed in the context of non-IBC probably had a positive impact on IBC patients.19 Several risk factors have been associated with the development of IBC: race (with higher incidence among black and Hispanic populations, and black women being diagnosed at a younger age); obesity; young age at first delivery; rural residence and longer cumulative duration of breastfeeding. Interestingly, IBC develops at a younger age compared to other forms of LABC and early stage breast cancer (mean age of 58.8 years, 66.2 years and 61.7 years, respectively).20–22
Pathobiology and prognostic factors
The histopathology of LABC, with its prevailing infiltrating ductal and lobular carcinomas is relatively similar to that of early stage disease. ‘Favourable’ histologies, such as tubular or medullary carcinomas, rarely present at an advanced stage unless they have been growing over a long period of time (neglected cases) and are more often encountered with advanced age.23,24 The prognostic role of hormone receptor status is similar to that in early stage disease, and positivity is 148 | MARCH 2015 | VOLUME 12
associated with better outcome.25 Compared to nonIBC, IBC is more frequently oestrogen receptor (ER) and progesterone receptor (PgR) negative. 26,27 ER expression remains an important prognostic factor for IBC; in the 1988–2000 SEER dataset, patients with ER‑positive IBC had longer median survival compared to patients with ER‑negative disease (4 years versus 2 years, P = 0.0001).22,26–28 Several specific molecular and biological features of IBC, such as its prominent angiogenic properties, reflect its aggressive behaviour and high metastatic potential.29 Increased mRNA expression of several angiogenic markers, including VEGF and its receptor VEGFR, have been demonstrated in IBC tissue samples. This angio invasive nature seems to be intrinsic to IBC and might constitute a rationale for specific treatment strategies.29,30 Interestingly, apart from high expression of VEGF‑D (a ligand of VEGFR‑3) in IBC, cell-line studies have also demonstrated increased levels of several other cytokines, such as bFGF, FGF‑2, IL‑6 and IL‑8 in addition to the most common ones, including IFN‑γ, IL‑1 and IL‑12.31–33 Primary IBC tumours are usually of high-grade ductal type, with atypical mitotic figures and high micro vessel density. A classic finding on the biopsy of affected skin is invasion of dermal lymphatics by the tumour cells. These tumour emboli are the main local signs of the disease and are thought to be responsible for its metastatic potential.34, 35 Two genes, RhoC GTPase and WISP3 (also known as lost in IBC, LIBC) were found to be altered in 91% of IBC cases.36,37 Overexpression of RhoC GTPase, whose gene product is involved in cytoskeleton reorganization, correlates with tumour progression and constitutes an important contributor to the IBC metastatic phenotype.36 The gene WISP3 encodes for an insulin-like growth factor binding protein-related protein (IGFBPrP). Downregulation or loss of IGFBPrP‑1 is associated with progression of IBC, whereas transfection of WISP3 into an inflammatory breast cancer cell line inhibited tumour growth, invasiveness and angiogenic potential, thus acting as a tumour suppressor gene.36,37 Several studies have also shown that IBC is often characterized by the high expression of genes associated with increased metabo lism and cell turnover, although these observations were only reported in a small number of cases and, therefore, no clear conclusions can be drawn. 38,39 Nonetheless, most of these studies confirm the genetic heterogeneity of IBC and the consistent biological differences between IBC and cancers of a non-IBC nature.28,38,39 A PAM50 analysis was conducted among 137 IBC (and 252 non-IBC cases), identifying all four intrinsic breast cancer subtypes; specifically, the luminal A subtype was less frequent than in non-IBC (19% versus 42%, P
