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Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer
original article
Annals of Oncology 21: 1974–1981, 2010 doi:10.1093/annonc/mdq072 Published online 23 March 2010
Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer
1 4
Research Unit in Medical Senology, Department of Medicine; 2Division of Epidemiology and Biostatistics and 3Division of Pathology, European Institute of Oncology; School of Medicine, University of Milan, Milan; 5Division of Senology; 6Department of Medicine, European Institute of Oncology, Milan, Italy
Received 4 December 2009; revised 12 February 2010; accepted 15 February 2010
Background: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women.
original article
Patients and methods: We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer. Results: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30–2.10 and HR = 1.78, 95% CI 1.12–2.85, respectively] when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B [HR = 1.62, 95% CI 1.21–2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96– 4.53 for overall survival (OS)] and with Triple Negative (HR = 2.04, 95% CI 1.11–3.72 for DFS and HR = 2.20, 95% CI 1.10–4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12–5.02) when compared with older patients. Conclusions: Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease. Key words: adjuvant therapy, breast cancer, prognostic features, very young women
introduction Breast cancer at a young age has been reported to pursue a more aggressive clinical behavior compared with the disease in older patients [1–4]. Although controversy exists about the definition of ‘very young age’ or ‘very young patients’ and different cut-off have been proposed, it has been shown that younger age is associated with a less favorable prognosis and that the relationship between recurrence hazard and age was continuous with a 4% decrease in recurrence and a 2% decrease in cancer-specific death for every year of increase in age [5]. In particular, in a recently published study, the risk of death rose by 5% for every 1-year reduction in age for patients aged <35 years, whereas there was no significant correlation between risk of death and age for patients aged 35–50 years [6]. *Correspondence to: Dr G. Cancello, Research Unit in Medical Senology, Department of Medicine, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489439; Fax: +39-02-574829212; E-mail: [email protected]
Breast cancer is a heterogeneous disease and gene expression studies have identified molecularly distinct subtypes with prognostic implications across multiple treatment settings [7– 9]. These subtypes include estrogen receptor (ER) positive—Luminal A (Luminal A), ER positive—Luminal B (Luminal B), HER2 enriched (i.e. tumors that overexpress ERBB2-associated genes but do not express genes that define the luminal subtype), Basal like and normal breast like. HER2enriched and Basal-like subtypes are hormone receptor negative and have poor prognosis [7, 10, 11]. The immunohistochemical evaluation of ER, progesterone receptor (PgR), Ki-67 and HER2 may be considered a surrogate means for identifying the molecular subtypes of breast cancer [12]. The classification according to four subtypes (Luminal A, Luminal B, HER2 and Triple Negative) appeared useful to define different prognostic subgroups with different relationship with adjuvant treatment received [13]. Whether the use of this classification for very young patients might be useful in clinical practice in order to accurately predict outcome is a hypothesis that has not been adequately tested.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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G. Cancello1*, P. Maisonneuve2, N. Rotmensz2, G. Viale3,4, M. G. Mastropasqua3, G. Pruneri3, P. Veronesi4,5, R. Torrisi1, E. Montagna1, A. Luini5, M. Intra5, O. Gentilini5, R. Ghisini1, A. Goldhirsch6 & M. Colleoni1
original article
Annals of Oncology
We therefore investigated the biological characteristics of the tumors and the outcome of very young patients (<35 years of age) with operable breast cancer and the effects of adjuvant treatment programs according to immunohistochemically (IHC) defined subtypes.
patients and methods
statistics The Fisher’s exact test and the Mantel–Haenszel chi-square test for trend were used to assess the association between, respectively, categorical and ordinal variables. The primary end points were the incidence of locoregional relapse (LRR), distant metastasis (DM), breast cancer-related event (BCE), disease-free survival (DFS) and overall survival (OS). DFS was defined as the length of time from the date of surgery to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer) or death, whichever occurred first. OS was determined as the time from surgery until the date of death (from any cause) or the date of last follow-up. Cumulative incidence and survival plots according to age were drawn using the Kaplan–Meier method. The log-rank test was used to assess the survival difference between strata. Multivariate Cox proportional hazard regression analysis was used to assess the independent prognostic significance of various clinical and histopathological characteristics of the tumor on event free or OS. Factors included in multiple regression analyses were tumor diameter, nodal involvement, ER and PgR expression, Ki-67 labeling index, HER2 overexpression, vascular invasion, grade, histotype and immunohistochemical classification as follows:
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Luminal A (ER > 0 or PgR > 0) and (Ki-67 < 14%) and (HER2 0/+/++), Luminal B (ER > 0 or PgR > 0) and [(Ki-67 ‡ 14%) or (HER2 +++)], HER2 positive (ER = 0 and PgR = 0) and (HER2 +++), and Triple Negative (ER = 0 and PgR = 0) and (HER2 0/+/++).
In patients with Luminal B tumors, we assessed the effect of adjuvant hormonal therapy on outcome. All analyses were carried out with the SAS software, version 8.2 (Cary, NC).
treatment received All patients received adequate local treatment (breast-conserving surgery or total mastectomy) plus axillary sentinel lymph node biopsy (SLNB) or complete axillary dissection. SLNB was followed by axillary dissection only if the sentinel node contained metastasis or minimal node involvement. The SLN was identified and isolated using a gamma probe as a guide as previously published [20]. Postoperative breast irradiation was proposed to all the patients who received breast-conserving surgery [21]. Systemic adjuvant therapy was recommended according to St. Gallen’s treatment guidelines [21–23]. For patients with endocrine-responsive disease, adjuvant endocrine therapy alone was indicated [the combination of tamoxifen for 5 years plus luteinizing hormone-releasing hormone (LHRH) analogue for a minimum of 2 years] [17]. In patients at higher risk (i.e. occurrence of PVI, younger age, large tumors) and/or with features of uncertain endocrine responsiveness (i.e. low levels of ER positivity, lack of PgR expression, overexpression of HER2/neu and increased proliferation markers [24]), chemotherapy was added. Anthracycline-containing chemotherapy was considered as the first option in patients with higher risk [i.e. adriamycin and cyclophosphamide (AC) for four courses [25], in case of comorbidities or patients preferences classical oral cyclophosphamide, methotrexate and fluorouracil (CMF)] for a duration of three to six courses was considered [26]. In case of endocrine non-responsive disease, 6 months of chemotherapy was commonly indicated (classical CMF for six courses or AC for four courses followed by classical CMF for three courses [19] according to the degree of the patient risk).
results A total of 4524 consecutive premenopausal patients aged <50 years were referred to the interdisciplinary evaluation and their data were included in the institutional database from 1997 to 2004. We subsequently excluded 1213 patients: 473 who received neoadjuvant therapy, 52 had a previous other primary, 136 had bilateral tumors, 552 were operated with recurrent or metastatic tumors and for the remaining 341 patients, endocrine receptor status, Ki-76 labeling index or HER2 status were not known, thus preventing the immunohistochemical subtyping of the tumors. The analysis is therefore on the basis of data from 2970 patients. The characteristics of the assessable patients are given in Table 1. In the ‘very young’ group, when compared with the ‘less young’ patients, there was a higher prevalence of tumors of high grade (57.1% versus 34.0%; P < 0.0001) and tumors classified ER (22.9% versus 12.8%; P < 0.0001) and PgR (32.1% versus 19.3%; P < 0.0001) absent. Moreover, in younger patients (aged <35 years), there were higher percentages of tumors with PVI (40.0% versus 33.5%; P = 0.02) and HER2overexpression (21% versus 14.5%; P = 0.003) than in patients aged 35–50 years.
doi:10.1093/annonc/mdq072 | 1975
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We revised data of premenopausal patients referred to surgery at the European Institute of Oncology from April 1997 to August 2000, already reported in a previous study [4]; additionally, we collected information of patients operated from September 2000 to December 2004. Data on the patient’s medical history, concurrent diseases, surgery, pathological evaluation and results of staging procedures (blood chemistry, hematological values, bone scan, chest film and upper abdominal ultrasound examination) were required. Pathological assessment included evaluation of the primary tumor size, histological type and of lymph nodes status, including a sentinel node biopsy [14], when applicable. Tumor grade was evaluated according to Elston and Ellis [15] and peritumoral vascular invasion (PVI) was assessed according to Rosen and Oberman [16]. ER and PgR status, Ki-67 labeling index (assessed with the MIB1 monoclonal antibody) and HER2 overexpression (routinely carried out since 1999) were evaluated IHC as previously reported [17]. The tumor sections were incubated with the specific primary mouse monoclonal antibodies to ER (clone 1D5, 1 : 100 dilution; Dako, Glostrup, Denmark) and PgR (clone 1A6, 1 : 800 dilution; Dako); Ki-67 was assessed using the MIB1 monoclonal antibody (1 : 200 dilution; Dako), and HER2 was evaluated using the polyclonal antibody by Dako (1 : 1600 dilution). The percentage of neoplastic cells showing definite nuclear immunoreactivity out of 2000 cells, in at least 10 high-power (magnification, ·400) fields randomly selected, was recorded for ER, PgR and Ki-67. For HER2 assessment, tumors were scored according to the intensity and completeness of cell membrane staining, in a 4-tier scale (0: no immunoreactivity, 1+: weak and incomplete membrane staining, 2+: weak/moderate and complete membrane staining and 3+: strong and complete membrane staining); furthermore, the percentage of immunoreactive neoplastic cells was recorded. Tumors scored 3+ were considered as overexpressing HER2. The threshold for ER and PgR positivity was 1% and for MIB1 positivity 20%, as previously published [17]. The threshold for ER and PgR was on the basis of published data, indicating a different pattern of outcomes according to the degree of potential endocrine responsiveness [18, 19].
original article
Annals of Oncology
Table 1. Characteristics of breast cancer patients according to age at diagnosis
1976 | Cancello et al.
Age at diagnosis (years) n (%) <35 ‡35
2970
315 (100.0)
2655 (100.0)
2398 253 120 199
283 7 4 21
(89.8) (2.2) (1.3) (6.7)
2115 246 116 178
(79.7) (9.3) (4.4) (6.7)
<0.0001
515 1286 906 227 36
33 129 115 34 4
(10.5) (41.0) (36.5) (10.8) (1.3)
482 1157 791 193 32
(18.2) (43.6) (29.8) (7.3) (1.2)
<0.0001
432 1348 1083 107
21 99 180 15
(6.7) (31.4) (57.1) (4.8)
411 1249 903 92
(15.5) (47.0) (34.0) (3.5)
<0.0001
1454 996 324 186 10
146 107 33 29 –
(46.3) (34.0) (10.5) (9.2)
1308 889 291 157 10
(49.3) (33.5) (11.0) (5.9) (0.4)
0.08
1951 1015 4
189 (60.0) 126 (40.0) 0 (0.0)
1762 (66.4) 889 (33.5) 4(0.2)
0.02
413 2557
72 (22.9) 243 (77.1)
341 (12.8) 2314 (87.2)
<0.0001
613 2357
101 (32.1) 214 (67.9)
512 (19.3) 2143 (80.7)
<0.0001
1173 1786 11
71 (22.5) 239 (75.9) 5 (1.6)
1102 (41.5) 1547 (58.3) 6 (0.2)
<0.0001
2144 451 375
208 (66.0) 66 (21.0) 41 (13.0)
1936 (72.9) 385 (14.5) 334 (12.6)
0.003
592 1986 1301 310 375 141 251
29 217 128 48 41 18 51
563 1769 1173 262 334 123 200
2194 776
227 (72.1) 88 (27.9)
1967 (74.1) 688 (25.9)
0.44
1123 1847
157 (49.8) 158 (50.2)
966 (36.4) 1689 (63.6)
<0.0001
(9.2) (68.9) (40.6) (15.2) (13.0) (5.7) (16.2)
P value
(21.2) (66.6) (44.2) (9.9) (12.6) (4.6) (7.5)
<0.0001
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All Histology Ductal Lobular Ductal + lobular Other Tumor size £1 cm 1–2 cm 2–4 cm >4 cm Unknown Tumor grade G1 G2 G3 Unknown Number of positive nodes None 1–3 4–9 10 or more pNx Peritumoral vascular invasion Absent Present Unknown Estrogen receptor Absent Present Progesterone receptor Absent Present Ki-67 <20% ‡20% Unknown HER2/neu 0/+/++ +++ Unknown Molecular classification Luminal A Luminal B Luminal B (HER2 0/+/++) Luminal B (HER2 +++) Luminal B (HER2 Unknown) HER2 Triple Negative Surgery Quadrantectomy Mastectomy Sentinel node biopsy No Yes
All patients
original article
Annals of Oncology
According to the immunohistochemical classification, in the group of patients aged <35 years, there were less tumors identified as Luminal A (9.2% versus 21.2%) and more Triple Negative tumors (16.2% versus 7.5%; P < 0.0001) than in older patients.
clinical outcomes according to age and IHC classification At the multivariate analysis, age <35 years was a risk factor for an increased occurrence of LRR [hazards ratio (HR) = 1.78, 95% confidence interval (CI) 1.19–2.67], DM (HR = 1.55, 95% CI 1.11–2.17) and BCEs (HR = 1.70, 95% CI 1.33–2.18) (Figure 1A). The outcome of younger patients with the Luminal A subtype was similar to that observed for the older patients in terms of LRR, DM and BCE. The difference between very young patients and older patients appeared evident in the Luminal B subtype with an increased risk of LRR (HR = 1.82, 95% CI 1.13–2.94), DM (HR = 1.57, 95% CI 1.04–2.37) and BCE (HR = 1.71, 95% CI 1.26–2.32) (Figure 1A). In the HER2 subtype, there was a trend to an increased risk of LRR and BCE and a statistically significant association with DM for very young patients when compared with older patients (Figure 1A), while in the
Table 2. Adjuvant treatment modalities in breast cancer patients according to age at diagnosis and molecular classification Luminal A <35 35–50 ALL 29 Hormonal therapy, n (%) None 2 (6.9) TAM alone 1 (3.4) LH-RH alone 3 (10.3) TAM + LHRH 22 (75.9) Other/NOS 1 (3.4) Chemotherapy, n (%) None 22 (75.9) Anthracycline 7 (24.1) CMF 0 (0.0) Other/NOS 0 (0.0)
Pa
563 12 84 18 431 18
(2.1) (14.9) (3.2) (76.6) (3.2)
430 102 17 14
(76.4) (18.1) (3.0) (2.5)
Luminal B <35
35–50
217
1769
0.036
16 8 29 162 2
(7.4) (3.7) (13.4) (74.7) (0.9)
80 428 48 1117 96
(4.5) (24.2) (2.7) (63.1) (5.4)
0.76
45 132 21 19
(20.7) (60.8) (9.7) (8.8)
702 776 197 94
(39.7) (43.9) (11.1) (5.3)
HER2 <35
35–50
18
123
<.0001
18 (100.) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
114 2 3 3 1
(92.7) (1.6) (2.4) (2.4) (0.8)
<.0001
1 14 1 2
11 81 8 23
(8.9) (65.9) (6.5) (18.7)
Pa
(5.6) (77.8) (5.6) (11.1)
Pa
Triple Negative <35 35–50 51
200
1.00
45 (88.2) 1 (2.0) 5 (9.8) 0 (0.0) 0 (0.0)
193 (96.5) 1 (0.5) 2 (1.0) 4 (2.0) 0 (0.0)
0.90
3 21 22 5
(5.9) (41.2) (43.1) (9.8)
13 87 88 12
(6.5) (43.5) (44.0) (6.0)
Pa
0.006
0.79
a
Fisher’s exact test. CMF, oral cyclophosphamide, methotrexate and fluorouracil; HER2; human epidermal growth factor receptor 2; LH-RH, luteinizing hormone-releasing hormone; NOS, not otherwise specified; TAM, tamoxifen.
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doi:10.1093/annonc/mdq072 | 1977
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adjuvant treatment As shown in Table 2, very young patients with the Luminal A subtype of breast cancer received more frequently LH-RH agonist alone and less frequently tamoxifen alone (P = 0.036) than older patients. In the Luminal B subtype, there were more patients aged <35 years treated with LH-RH alone and with the combination of tamoxifen and LH-RH analogue than older patients (P < 0.0001). Moreover, younger patients with a Luminal B tumor received more anthracyclines-based chemotherapy than older patients (P < 0.0001). No significant difference was seen in the treatment of patients with HER2 and Triple Negative subtypes.
Triple Negative subtype, a statistically significant association was showed with BCE. At the multivariate analysis, age <35 years was a risk factor for reduced DFS (HR = 1.65, 95% CI 1.30–2.10) and OS (HR = 1.78, 95% CI 1.12–2.85) (Figure 1B). Very young patients with tumors classified as Luminal B, HER2 and Triple Negative were at increased risk of poorer DFS (HR = 1.62, 95% CI 1.21–2.18; HR = 2.37, 95% CI 1.12–5.02 and HR = 2.04, 95% CI 1.11–3.72, respectively), while in the Luminal B and Triple Negative subtypes, patients <35 years had a twofold higher risk of death compared with older patients (HR = 2.09, 95% CI 0.96–4.53 and HR = 2.20, 95% CI 1.10– 4.41, respectively) (Figure 1B). We have analyzed clinical outcomes with stratification of Luminal B according to HER2 expression (Table 1). Very young patients with tumors defined as Luminal B (HER2 0/+/++) were at increased risk of LRR, BCEs and recurrence compared with older patients. No statistically significant difference was shown between the two groups of age in the Luminal B (HER2 +++) subtype (Figure 1 bis—Supplementary data available in Annals of Oncology online). An exploratory analysis was conducted to evaluate the impact of the different adjuvant therapies on DFS of very young and older patients with tumors defined as Luminal B. A statistically significant reduced DFS was seen in younger patients with tumors defined as Luminal B who received tamoxifen or LH-RH analogue alone versus those treated with the combination of the two drugs (P = 0.037). The result was confirmed at the multivariate analysis (HR = 1.88, 95% CI 1.00–3.55), whereas no treatment effect was observed within this subtype in older patients (P = 0.77; HR = 0.97, 95% CI 0.70–1.34) (Figure 2). Our data showed a reduced DFS of patients <35 years who received tamoxifen or LH-RH analogue alone versus those treated with the combination of the two drugs in the Luminal B (HER2 0/+/++) and in the Luminal B (HER2 +++) subtype, but this difference was not statistically significant (Table 2 bis and Figure 2 bis—Supplementary data available in Annals of Oncology online).
original article
Annals of Oncology
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Figure 1. (A) Cumulative incidence (%) of locoregional relapse, distant metastases and breast cancer-related events in breast cancer patients according to age at diagnosis and immunohistochemical classification. (B) Disease-free survival and overall survival in breast cancer patients according to age at diagnosis and immunohistochemical classification. Hazards ratios (HR) and 95% confidence intervals (CI) obtained from multivariable Cox proportional hazards regression model adjusted for hormonal receptor status, proliferative index (Ki-67), peritumoral vascular invasion, tumor size, nodal status and HER2 overexpression, chemotherapy (none/oral cyclophosphamide, methotrexate and fluorouracil/anthracycline-containing therapy and other regimen) and hormonal therapy (none, luteinizing hormone-releasing hormone (LH-RH) or tamoxifen alone, LH-RH + tamoxifen and other regimen); n/a: not available.
As a final point, multivariate analysis showed a slight advantage of anthracycline-containing therapy compared with CMF regimen for both very young and older patients in terms of DFS, even if no statistically significant difference was found (Table 2 bis and Figure 2 ter—Supplementary data available in Annals of Oncology online).
1978 | Cancello et al.
discussion The present study provides useful insights into the treatment of breast cancer because it is on the basis of a large population of very young patients with breast cancer evaluated within the context of a central pathology analysis using modern
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Annals of Oncology
original article
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Figure 1. (Continued)
classification according to IHC-defined subtypes. In fact, as recently showed, an IHC profile on the basis of the degree of expression of ER, PgR, Ki-67 and HER2 might identify subgroups of breast cancer patients who will respond to
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different systemic adjuvant treatments [13]. However, limited information is available in the adjuvant setting on the outcome and responsiveness to therapy in the very young population.
doi:10.1093/annonc/mdq072 | 1979
original article
Annals of Oncology
Our study showed that in the group of patients aged <35 years, there were less tumors defined as Luminal A and more Triple Negative tumors than older patients. Results from other studies also showed a relationship between age and breast cancer subtypes. In particular, in the Carolina Breast Cancer Study, Luminal A and B subtypes were more frequently observed in postmenopausal patients than in premenopausal African American women [27]. Conversely, patients with the Triple Negative subtype were likely to be under the age of 40 years in another study [28]. Beside the feature of a more aggressive disease presentation, which affects patients’ outcome, the results of the present study led to the identification of IHC-defined subtypes within the group of very young patients, which require adjuvant tailored therapies. In fact, our study showed that very young patients with tumors classified as Luminal B, HER2 and Triple Negative subtype were at increased risk of LRR, DM, BCE, recurrence and death when compared with older patients. Conversely, no significant effect of age was registered in the subgroup of patients with the Luminal A subtype. The results observed in terms of low number of events and similar outcome of older patients might be useful when a therapeutic algorithm should be developed in young patients with Luminal A breast cancer candidate to adjuvant treatment. The results of this analysis are important also for clarifying the role of endocrine treatments in younger patients. In particular, whether the use of the combination of ovarian function suppression plus tamoxifen may be a preferable solution for these patients is a hypothesis that has not been tested adequately. Endocrine therapies appear to be an essential component of an effective adjuvant therapy program and retrospective analyses indicate that the endocrine effects of chemotherapy alone are insufficient for the younger patients with endocrine-responsive breast cancer [29]. A large analysis on 7631 patients who were treated with chemotherapy alone showed markedly increased risks of relapse for young patients with ER-positive tumors compared with older patients [29]. In a retrospective analysis of 3700 premenopausal patients involved in International Breast Cancer Study Group trials I, II, V and VI patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy alone, the failure to achieve chemotherapy-
1980 | Cancello et al.
induced amenorrhea was associated with an increased risk of relapse [30]. Moreover, Ahn et al. [31] showed that adjuvant tamoxifen significantly reduced the death risk (HR = 0.61) among patients aged between 35 and 50 years of age with positive or unknown hormone receptor status, but there was no significant benefit from tamoxifen in patients <35 years. Similarly, data from the National Surgical Adjuvant Breast and Bowel Project indicate an increased risk (HR = 1.91, 95% CI 1.21–3.01; P = 0.006) for younger versus older patients with endocrineresponsive disease treated with tamoxifen alone [32]. In the present study, we found that for very young patients (aged <35 years) with the Luminal B subtype, the combination of LH-RH analogue and tamoxifen was significantly correlated with improved DFS when compared with either tamoxifen or LH-RH analogue alone. Our results show that the benefit of the addition of LH-RH analogue to tamoxifen is restricted to the Luminal B population, and no clear beneficial effect for the combination was observed in the subgroup of patients with Luminal A subtype. There are several potential reasons for explaining the different response to endocrine therapy according to Luminal subtype. The different responsiveness observed might be related to the limited number of events observed within the Luminal A subtype. Moreover, a beneficial effect for adjuvant ovarian function suppression was observed in a large study for patients with HER2-positive disease, a population included in the Luminal B subtype but not in the Luminal A subgroup [33]; when we stratified the Luminal B subtype according HER2 overexpression, we found that the beneficial effect of the combination LH-RH analogue plus tamoxifen was larger in the HER2-positive disease. The question of whether additional benefit can be obtained from ovarian suppression in premenopausal patients receiving tamoxifen is now being directly addressed by the global Suppression of Ovarian Function Trial (SOFT) coordinated by the IBCSG on behalf of the Breast International Group and the North American Breast Cancer Intergroup. SOFT compares tamoxifen alone versus ovarian function suppression plus tamoxifen versus ovarian function suppression plus exemestane for patients with steroid hormone receptor-positive tumors who remain premenopausal after adjuvant chemotherapy or
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Figure 2. Disease-free survival according to selected adjuvant therapies in Luminal B breast cancer according to age at diagnosis. Hazards ratios (HR) and 95% confidence intervals (CI) for luteinizing hormone-releasing hormone (LH-RH) or tamoxifen alone versus LH-RH + tamoxifen (HR) obtained from multivariable Cox proportional hazards regression model adjusted for proliferative index (Ki-67), peritumoral vascular invasion, tumor size, nodal status and HER2 overexpression.
Annals of Oncology
for whom tamoxifen alone is considered reasonable treatment option. In conclusion, the present study indicates that the outcome of very young patients with early breast cancer is worse in selected tumor subtypes identified by IHC. Moreover, the results presented in this study support the hypothesis that the progress in the adjuvant treatment of very young patients requires study of tailored treatments in specific ‘niches’ of patients. It should, however, be emphasized, however, that the tumor subtypes identified in the current study still include heterogeneous groups of tumors and that the identification of further tumor subtypes amenable to targeted treatments represents a research priority.
None of the authors declare conflicts of interest.
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16. Rosen PP, Oberman HA. Tumors of the Mammary Gland. Washington DC: Armed Forces Institute of Pathology 1993. 17. Viale G, Regan MM, Mastropasqua MG et al. Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst 2008; 100: 207–212. 18. Harvey JM, Clark GM, Osborne CK et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474–1481. 19. Colleoni M, Gelber S, Goldhirsch A et al. Tamoxifen after adjuvant chemotherapy for premenopausal patients with lymph-node positive breast cancer: International Breast Cancer Study Group Trial 13. J Clin Oncol 2006; 20: 1332–1341. 20. Veronesi U, Paganelli G, Viale G et al. A randomized comparison of sentinel node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003; 349: 546–553. 21. Goldhirsch A, Wood WC, Senn HJ et al. Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1995; 87: 1441–1445. 22. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998; 90: 1601–1608. 23. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 2001; 19: 3817–3827. 24. Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16: 1569–1583. 25. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicincyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumours: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8: 1483–1496. 26. Colleoni M, Litman HJ, Castiglione-Gertsch M et al. Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomised trials investigating three versus six courses of CMF. Br J Cancer 2002; 86: 1705–1714. 27. Carey LA, Perou CM, Livasy CA et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: 2492–2502. 28. Bauer KR, Brown M, Cress RD et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 2007; 109: 1721–1728. 29. Goldhirsch A, Gelber RD, Yothers G et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr 2001; 30: 44–51. 30. Aebi S, Gelber S, Castiglione-Gertsch M et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000; 355: 1869–1874. 31. Ahn SH, Son BH, Kim SW et al. Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea–a report from the Korean Breast Cancer Society. J Clin Oncol 2007; 25: 2360–2368. 32. Fisher B, Costantino J, Redmond C et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989; 320: 479–484. 33. Love RR, Duc NB, Havighurst TC et al. Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. J Clin Oncol 2003; 21: 453–457.
doi:10.1093/annonc/mdq072 | 1981
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disclosure
original article
Annals of Oncology 21: 1974–1981, 2010 doi:10.1093/annonc/mdq072 Published online 23 March 2010
Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer
1 4
Research Unit in Medical Senology, Department of Medicine; 2Division of Epidemiology and Biostatistics and 3Division of Pathology, European Institute of Oncology; School of Medicine, University of Milan, Milan; 5Division of Senology; 6Department of Medicine, European Institute of Oncology, Milan, Italy
Received 4 December 2009; revised 12 February 2010; accepted 15 February 2010
Background: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women.
original article
Patients and methods: We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer. Results: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30–2.10 and HR = 1.78, 95% CI 1.12–2.85, respectively] when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B [HR = 1.62, 95% CI 1.21–2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96– 4.53 for overall survival (OS)] and with Triple Negative (HR = 2.04, 95% CI 1.11–3.72 for DFS and HR = 2.20, 95% CI 1.10–4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12–5.02) when compared with older patients. Conclusions: Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease. Key words: adjuvant therapy, breast cancer, prognostic features, very young women
introduction Breast cancer at a young age has been reported to pursue a more aggressive clinical behavior compared with the disease in older patients [1–4]. Although controversy exists about the definition of ‘very young age’ or ‘very young patients’ and different cut-off have been proposed, it has been shown that younger age is associated with a less favorable prognosis and that the relationship between recurrence hazard and age was continuous with a 4% decrease in recurrence and a 2% decrease in cancer-specific death for every year of increase in age [5]. In particular, in a recently published study, the risk of death rose by 5% for every 1-year reduction in age for patients aged <35 years, whereas there was no significant correlation between risk of death and age for patients aged 35–50 years [6]. *Correspondence to: Dr G. Cancello, Research Unit in Medical Senology, Department of Medicine, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489439; Fax: +39-02-574829212; E-mail: [email protected]
Breast cancer is a heterogeneous disease and gene expression studies have identified molecularly distinct subtypes with prognostic implications across multiple treatment settings [7– 9]. These subtypes include estrogen receptor (ER) positive—Luminal A (Luminal A), ER positive—Luminal B (Luminal B), HER2 enriched (i.e. tumors that overexpress ERBB2-associated genes but do not express genes that define the luminal subtype), Basal like and normal breast like. HER2enriched and Basal-like subtypes are hormone receptor negative and have poor prognosis [7, 10, 11]. The immunohistochemical evaluation of ER, progesterone receptor (PgR), Ki-67 and HER2 may be considered a surrogate means for identifying the molecular subtypes of breast cancer [12]. The classification according to four subtypes (Luminal A, Luminal B, HER2 and Triple Negative) appeared useful to define different prognostic subgroups with different relationship with adjuvant treatment received [13]. Whether the use of this classification for very young patients might be useful in clinical practice in order to accurately predict outcome is a hypothesis that has not been adequately tested.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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G. Cancello1*, P. Maisonneuve2, N. Rotmensz2, G. Viale3,4, M. G. Mastropasqua3, G. Pruneri3, P. Veronesi4,5, R. Torrisi1, E. Montagna1, A. Luini5, M. Intra5, O. Gentilini5, R. Ghisini1, A. Goldhirsch6 & M. Colleoni1
original article
Annals of Oncology
We therefore investigated the biological characteristics of the tumors and the outcome of very young patients (<35 years of age) with operable breast cancer and the effects of adjuvant treatment programs according to immunohistochemically (IHC) defined subtypes.
patients and methods
statistics The Fisher’s exact test and the Mantel–Haenszel chi-square test for trend were used to assess the association between, respectively, categorical and ordinal variables. The primary end points were the incidence of locoregional relapse (LRR), distant metastasis (DM), breast cancer-related event (BCE), disease-free survival (DFS) and overall survival (OS). DFS was defined as the length of time from the date of surgery to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer) or death, whichever occurred first. OS was determined as the time from surgery until the date of death (from any cause) or the date of last follow-up. Cumulative incidence and survival plots according to age were drawn using the Kaplan–Meier method. The log-rank test was used to assess the survival difference between strata. Multivariate Cox proportional hazard regression analysis was used to assess the independent prognostic significance of various clinical and histopathological characteristics of the tumor on event free or OS. Factors included in multiple regression analyses were tumor diameter, nodal involvement, ER and PgR expression, Ki-67 labeling index, HER2 overexpression, vascular invasion, grade, histotype and immunohistochemical classification as follows:
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Luminal A (ER > 0 or PgR > 0) and (Ki-67 < 14%) and (HER2 0/+/++), Luminal B (ER > 0 or PgR > 0) and [(Ki-67 ‡ 14%) or (HER2 +++)], HER2 positive (ER = 0 and PgR = 0) and (HER2 +++), and Triple Negative (ER = 0 and PgR = 0) and (HER2 0/+/++).
In patients with Luminal B tumors, we assessed the effect of adjuvant hormonal therapy on outcome. All analyses were carried out with the SAS software, version 8.2 (Cary, NC).
treatment received All patients received adequate local treatment (breast-conserving surgery or total mastectomy) plus axillary sentinel lymph node biopsy (SLNB) or complete axillary dissection. SLNB was followed by axillary dissection only if the sentinel node contained metastasis or minimal node involvement. The SLN was identified and isolated using a gamma probe as a guide as previously published [20]. Postoperative breast irradiation was proposed to all the patients who received breast-conserving surgery [21]. Systemic adjuvant therapy was recommended according to St. Gallen’s treatment guidelines [21–23]. For patients with endocrine-responsive disease, adjuvant endocrine therapy alone was indicated [the combination of tamoxifen for 5 years plus luteinizing hormone-releasing hormone (LHRH) analogue for a minimum of 2 years] [17]. In patients at higher risk (i.e. occurrence of PVI, younger age, large tumors) and/or with features of uncertain endocrine responsiveness (i.e. low levels of ER positivity, lack of PgR expression, overexpression of HER2/neu and increased proliferation markers [24]), chemotherapy was added. Anthracycline-containing chemotherapy was considered as the first option in patients with higher risk [i.e. adriamycin and cyclophosphamide (AC) for four courses [25], in case of comorbidities or patients preferences classical oral cyclophosphamide, methotrexate and fluorouracil (CMF)] for a duration of three to six courses was considered [26]. In case of endocrine non-responsive disease, 6 months of chemotherapy was commonly indicated (classical CMF for six courses or AC for four courses followed by classical CMF for three courses [19] according to the degree of the patient risk).
results A total of 4524 consecutive premenopausal patients aged <50 years were referred to the interdisciplinary evaluation and their data were included in the institutional database from 1997 to 2004. We subsequently excluded 1213 patients: 473 who received neoadjuvant therapy, 52 had a previous other primary, 136 had bilateral tumors, 552 were operated with recurrent or metastatic tumors and for the remaining 341 patients, endocrine receptor status, Ki-76 labeling index or HER2 status were not known, thus preventing the immunohistochemical subtyping of the tumors. The analysis is therefore on the basis of data from 2970 patients. The characteristics of the assessable patients are given in Table 1. In the ‘very young’ group, when compared with the ‘less young’ patients, there was a higher prevalence of tumors of high grade (57.1% versus 34.0%; P < 0.0001) and tumors classified ER (22.9% versus 12.8%; P < 0.0001) and PgR (32.1% versus 19.3%; P < 0.0001) absent. Moreover, in younger patients (aged <35 years), there were higher percentages of tumors with PVI (40.0% versus 33.5%; P = 0.02) and HER2overexpression (21% versus 14.5%; P = 0.003) than in patients aged 35–50 years.
doi:10.1093/annonc/mdq072 | 1975
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We revised data of premenopausal patients referred to surgery at the European Institute of Oncology from April 1997 to August 2000, already reported in a previous study [4]; additionally, we collected information of patients operated from September 2000 to December 2004. Data on the patient’s medical history, concurrent diseases, surgery, pathological evaluation and results of staging procedures (blood chemistry, hematological values, bone scan, chest film and upper abdominal ultrasound examination) were required. Pathological assessment included evaluation of the primary tumor size, histological type and of lymph nodes status, including a sentinel node biopsy [14], when applicable. Tumor grade was evaluated according to Elston and Ellis [15] and peritumoral vascular invasion (PVI) was assessed according to Rosen and Oberman [16]. ER and PgR status, Ki-67 labeling index (assessed with the MIB1 monoclonal antibody) and HER2 overexpression (routinely carried out since 1999) were evaluated IHC as previously reported [17]. The tumor sections were incubated with the specific primary mouse monoclonal antibodies to ER (clone 1D5, 1 : 100 dilution; Dako, Glostrup, Denmark) and PgR (clone 1A6, 1 : 800 dilution; Dako); Ki-67 was assessed using the MIB1 monoclonal antibody (1 : 200 dilution; Dako), and HER2 was evaluated using the polyclonal antibody by Dako (1 : 1600 dilution). The percentage of neoplastic cells showing definite nuclear immunoreactivity out of 2000 cells, in at least 10 high-power (magnification, ·400) fields randomly selected, was recorded for ER, PgR and Ki-67. For HER2 assessment, tumors were scored according to the intensity and completeness of cell membrane staining, in a 4-tier scale (0: no immunoreactivity, 1+: weak and incomplete membrane staining, 2+: weak/moderate and complete membrane staining and 3+: strong and complete membrane staining); furthermore, the percentage of immunoreactive neoplastic cells was recorded. Tumors scored 3+ were considered as overexpressing HER2. The threshold for ER and PgR positivity was 1% and for MIB1 positivity 20%, as previously published [17]. The threshold for ER and PgR was on the basis of published data, indicating a different pattern of outcomes according to the degree of potential endocrine responsiveness [18, 19].
original article
Annals of Oncology
Table 1. Characteristics of breast cancer patients according to age at diagnosis
1976 | Cancello et al.
Age at diagnosis (years) n (%) <35 ‡35
2970
315 (100.0)
2655 (100.0)
2398 253 120 199
283 7 4 21
(89.8) (2.2) (1.3) (6.7)
2115 246 116 178
(79.7) (9.3) (4.4) (6.7)
<0.0001
515 1286 906 227 36
33 129 115 34 4
(10.5) (41.0) (36.5) (10.8) (1.3)
482 1157 791 193 32
(18.2) (43.6) (29.8) (7.3) (1.2)
<0.0001
432 1348 1083 107
21 99 180 15
(6.7) (31.4) (57.1) (4.8)
411 1249 903 92
(15.5) (47.0) (34.0) (3.5)
<0.0001
1454 996 324 186 10
146 107 33 29 –
(46.3) (34.0) (10.5) (9.2)
1308 889 291 157 10
(49.3) (33.5) (11.0) (5.9) (0.4)
0.08
1951 1015 4
189 (60.0) 126 (40.0) 0 (0.0)
1762 (66.4) 889 (33.5) 4(0.2)
0.02
413 2557
72 (22.9) 243 (77.1)
341 (12.8) 2314 (87.2)
<0.0001
613 2357
101 (32.1) 214 (67.9)
512 (19.3) 2143 (80.7)
<0.0001
1173 1786 11
71 (22.5) 239 (75.9) 5 (1.6)
1102 (41.5) 1547 (58.3) 6 (0.2)
<0.0001
2144 451 375
208 (66.0) 66 (21.0) 41 (13.0)
1936 (72.9) 385 (14.5) 334 (12.6)
0.003
592 1986 1301 310 375 141 251
29 217 128 48 41 18 51
563 1769 1173 262 334 123 200
2194 776
227 (72.1) 88 (27.9)
1967 (74.1) 688 (25.9)
0.44
1123 1847
157 (49.8) 158 (50.2)
966 (36.4) 1689 (63.6)
<0.0001
(9.2) (68.9) (40.6) (15.2) (13.0) (5.7) (16.2)
P value
(21.2) (66.6) (44.2) (9.9) (12.6) (4.6) (7.5)
<0.0001
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All Histology Ductal Lobular Ductal + lobular Other Tumor size £1 cm 1–2 cm 2–4 cm >4 cm Unknown Tumor grade G1 G2 G3 Unknown Number of positive nodes None 1–3 4–9 10 or more pNx Peritumoral vascular invasion Absent Present Unknown Estrogen receptor Absent Present Progesterone receptor Absent Present Ki-67 <20% ‡20% Unknown HER2/neu 0/+/++ +++ Unknown Molecular classification Luminal A Luminal B Luminal B (HER2 0/+/++) Luminal B (HER2 +++) Luminal B (HER2 Unknown) HER2 Triple Negative Surgery Quadrantectomy Mastectomy Sentinel node biopsy No Yes
All patients
original article
Annals of Oncology
According to the immunohistochemical classification, in the group of patients aged <35 years, there were less tumors identified as Luminal A (9.2% versus 21.2%) and more Triple Negative tumors (16.2% versus 7.5%; P < 0.0001) than in older patients.
clinical outcomes according to age and IHC classification At the multivariate analysis, age <35 years was a risk factor for an increased occurrence of LRR [hazards ratio (HR) = 1.78, 95% confidence interval (CI) 1.19–2.67], DM (HR = 1.55, 95% CI 1.11–2.17) and BCEs (HR = 1.70, 95% CI 1.33–2.18) (Figure 1A). The outcome of younger patients with the Luminal A subtype was similar to that observed for the older patients in terms of LRR, DM and BCE. The difference between very young patients and older patients appeared evident in the Luminal B subtype with an increased risk of LRR (HR = 1.82, 95% CI 1.13–2.94), DM (HR = 1.57, 95% CI 1.04–2.37) and BCE (HR = 1.71, 95% CI 1.26–2.32) (Figure 1A). In the HER2 subtype, there was a trend to an increased risk of LRR and BCE and a statistically significant association with DM for very young patients when compared with older patients (Figure 1A), while in the
Table 2. Adjuvant treatment modalities in breast cancer patients according to age at diagnosis and molecular classification Luminal A <35 35–50 ALL 29 Hormonal therapy, n (%) None 2 (6.9) TAM alone 1 (3.4) LH-RH alone 3 (10.3) TAM + LHRH 22 (75.9) Other/NOS 1 (3.4) Chemotherapy, n (%) None 22 (75.9) Anthracycline 7 (24.1) CMF 0 (0.0) Other/NOS 0 (0.0)
Pa
563 12 84 18 431 18
(2.1) (14.9) (3.2) (76.6) (3.2)
430 102 17 14
(76.4) (18.1) (3.0) (2.5)
Luminal B <35
35–50
217
1769
0.036
16 8 29 162 2
(7.4) (3.7) (13.4) (74.7) (0.9)
80 428 48 1117 96
(4.5) (24.2) (2.7) (63.1) (5.4)
0.76
45 132 21 19
(20.7) (60.8) (9.7) (8.8)
702 776 197 94
(39.7) (43.9) (11.1) (5.3)
HER2 <35
35–50
18
123
<.0001
18 (100.) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
114 2 3 3 1
(92.7) (1.6) (2.4) (2.4) (0.8)
<.0001
1 14 1 2
11 81 8 23
(8.9) (65.9) (6.5) (18.7)
Pa
(5.6) (77.8) (5.6) (11.1)
Pa
Triple Negative <35 35–50 51
200
1.00
45 (88.2) 1 (2.0) 5 (9.8) 0 (0.0) 0 (0.0)
193 (96.5) 1 (0.5) 2 (1.0) 4 (2.0) 0 (0.0)
0.90
3 21 22 5
(5.9) (41.2) (43.1) (9.8)
13 87 88 12
(6.5) (43.5) (44.0) (6.0)
Pa
0.006
0.79
a
Fisher’s exact test. CMF, oral cyclophosphamide, methotrexate and fluorouracil; HER2; human epidermal growth factor receptor 2; LH-RH, luteinizing hormone-releasing hormone; NOS, not otherwise specified; TAM, tamoxifen.
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doi:10.1093/annonc/mdq072 | 1977
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adjuvant treatment As shown in Table 2, very young patients with the Luminal A subtype of breast cancer received more frequently LH-RH agonist alone and less frequently tamoxifen alone (P = 0.036) than older patients. In the Luminal B subtype, there were more patients aged <35 years treated with LH-RH alone and with the combination of tamoxifen and LH-RH analogue than older patients (P < 0.0001). Moreover, younger patients with a Luminal B tumor received more anthracyclines-based chemotherapy than older patients (P < 0.0001). No significant difference was seen in the treatment of patients with HER2 and Triple Negative subtypes.
Triple Negative subtype, a statistically significant association was showed with BCE. At the multivariate analysis, age <35 years was a risk factor for reduced DFS (HR = 1.65, 95% CI 1.30–2.10) and OS (HR = 1.78, 95% CI 1.12–2.85) (Figure 1B). Very young patients with tumors classified as Luminal B, HER2 and Triple Negative were at increased risk of poorer DFS (HR = 1.62, 95% CI 1.21–2.18; HR = 2.37, 95% CI 1.12–5.02 and HR = 2.04, 95% CI 1.11–3.72, respectively), while in the Luminal B and Triple Negative subtypes, patients <35 years had a twofold higher risk of death compared with older patients (HR = 2.09, 95% CI 0.96–4.53 and HR = 2.20, 95% CI 1.10– 4.41, respectively) (Figure 1B). We have analyzed clinical outcomes with stratification of Luminal B according to HER2 expression (Table 1). Very young patients with tumors defined as Luminal B (HER2 0/+/++) were at increased risk of LRR, BCEs and recurrence compared with older patients. No statistically significant difference was shown between the two groups of age in the Luminal B (HER2 +++) subtype (Figure 1 bis—Supplementary data available in Annals of Oncology online). An exploratory analysis was conducted to evaluate the impact of the different adjuvant therapies on DFS of very young and older patients with tumors defined as Luminal B. A statistically significant reduced DFS was seen in younger patients with tumors defined as Luminal B who received tamoxifen or LH-RH analogue alone versus those treated with the combination of the two drugs (P = 0.037). The result was confirmed at the multivariate analysis (HR = 1.88, 95% CI 1.00–3.55), whereas no treatment effect was observed within this subtype in older patients (P = 0.77; HR = 0.97, 95% CI 0.70–1.34) (Figure 2). Our data showed a reduced DFS of patients <35 years who received tamoxifen or LH-RH analogue alone versus those treated with the combination of the two drugs in the Luminal B (HER2 0/+/++) and in the Luminal B (HER2 +++) subtype, but this difference was not statistically significant (Table 2 bis and Figure 2 bis—Supplementary data available in Annals of Oncology online).
original article
Annals of Oncology
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Figure 1. (A) Cumulative incidence (%) of locoregional relapse, distant metastases and breast cancer-related events in breast cancer patients according to age at diagnosis and immunohistochemical classification. (B) Disease-free survival and overall survival in breast cancer patients according to age at diagnosis and immunohistochemical classification. Hazards ratios (HR) and 95% confidence intervals (CI) obtained from multivariable Cox proportional hazards regression model adjusted for hormonal receptor status, proliferative index (Ki-67), peritumoral vascular invasion, tumor size, nodal status and HER2 overexpression, chemotherapy (none/oral cyclophosphamide, methotrexate and fluorouracil/anthracycline-containing therapy and other regimen) and hormonal therapy (none, luteinizing hormone-releasing hormone (LH-RH) or tamoxifen alone, LH-RH + tamoxifen and other regimen); n/a: not available.
As a final point, multivariate analysis showed a slight advantage of anthracycline-containing therapy compared with CMF regimen for both very young and older patients in terms of DFS, even if no statistically significant difference was found (Table 2 bis and Figure 2 ter—Supplementary data available in Annals of Oncology online).
1978 | Cancello et al.
discussion The present study provides useful insights into the treatment of breast cancer because it is on the basis of a large population of very young patients with breast cancer evaluated within the context of a central pathology analysis using modern
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Annals of Oncology
original article
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Figure 1. (Continued)
classification according to IHC-defined subtypes. In fact, as recently showed, an IHC profile on the basis of the degree of expression of ER, PgR, Ki-67 and HER2 might identify subgroups of breast cancer patients who will respond to
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different systemic adjuvant treatments [13]. However, limited information is available in the adjuvant setting on the outcome and responsiveness to therapy in the very young population.
doi:10.1093/annonc/mdq072 | 1979
original article
Annals of Oncology
Our study showed that in the group of patients aged <35 years, there were less tumors defined as Luminal A and more Triple Negative tumors than older patients. Results from other studies also showed a relationship between age and breast cancer subtypes. In particular, in the Carolina Breast Cancer Study, Luminal A and B subtypes were more frequently observed in postmenopausal patients than in premenopausal African American women [27]. Conversely, patients with the Triple Negative subtype were likely to be under the age of 40 years in another study [28]. Beside the feature of a more aggressive disease presentation, which affects patients’ outcome, the results of the present study led to the identification of IHC-defined subtypes within the group of very young patients, which require adjuvant tailored therapies. In fact, our study showed that very young patients with tumors classified as Luminal B, HER2 and Triple Negative subtype were at increased risk of LRR, DM, BCE, recurrence and death when compared with older patients. Conversely, no significant effect of age was registered in the subgroup of patients with the Luminal A subtype. The results observed in terms of low number of events and similar outcome of older patients might be useful when a therapeutic algorithm should be developed in young patients with Luminal A breast cancer candidate to adjuvant treatment. The results of this analysis are important also for clarifying the role of endocrine treatments in younger patients. In particular, whether the use of the combination of ovarian function suppression plus tamoxifen may be a preferable solution for these patients is a hypothesis that has not been tested adequately. Endocrine therapies appear to be an essential component of an effective adjuvant therapy program and retrospective analyses indicate that the endocrine effects of chemotherapy alone are insufficient for the younger patients with endocrine-responsive breast cancer [29]. A large analysis on 7631 patients who were treated with chemotherapy alone showed markedly increased risks of relapse for young patients with ER-positive tumors compared with older patients [29]. In a retrospective analysis of 3700 premenopausal patients involved in International Breast Cancer Study Group trials I, II, V and VI patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy alone, the failure to achieve chemotherapy-
1980 | Cancello et al.
induced amenorrhea was associated with an increased risk of relapse [30]. Moreover, Ahn et al. [31] showed that adjuvant tamoxifen significantly reduced the death risk (HR = 0.61) among patients aged between 35 and 50 years of age with positive or unknown hormone receptor status, but there was no significant benefit from tamoxifen in patients <35 years. Similarly, data from the National Surgical Adjuvant Breast and Bowel Project indicate an increased risk (HR = 1.91, 95% CI 1.21–3.01; P = 0.006) for younger versus older patients with endocrineresponsive disease treated with tamoxifen alone [32]. In the present study, we found that for very young patients (aged <35 years) with the Luminal B subtype, the combination of LH-RH analogue and tamoxifen was significantly correlated with improved DFS when compared with either tamoxifen or LH-RH analogue alone. Our results show that the benefit of the addition of LH-RH analogue to tamoxifen is restricted to the Luminal B population, and no clear beneficial effect for the combination was observed in the subgroup of patients with Luminal A subtype. There are several potential reasons for explaining the different response to endocrine therapy according to Luminal subtype. The different responsiveness observed might be related to the limited number of events observed within the Luminal A subtype. Moreover, a beneficial effect for adjuvant ovarian function suppression was observed in a large study for patients with HER2-positive disease, a population included in the Luminal B subtype but not in the Luminal A subgroup [33]; when we stratified the Luminal B subtype according HER2 overexpression, we found that the beneficial effect of the combination LH-RH analogue plus tamoxifen was larger in the HER2-positive disease. The question of whether additional benefit can be obtained from ovarian suppression in premenopausal patients receiving tamoxifen is now being directly addressed by the global Suppression of Ovarian Function Trial (SOFT) coordinated by the IBCSG on behalf of the Breast International Group and the North American Breast Cancer Intergroup. SOFT compares tamoxifen alone versus ovarian function suppression plus tamoxifen versus ovarian function suppression plus exemestane for patients with steroid hormone receptor-positive tumors who remain premenopausal after adjuvant chemotherapy or
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Figure 2. Disease-free survival according to selected adjuvant therapies in Luminal B breast cancer according to age at diagnosis. Hazards ratios (HR) and 95% confidence intervals (CI) for luteinizing hormone-releasing hormone (LH-RH) or tamoxifen alone versus LH-RH + tamoxifen (HR) obtained from multivariable Cox proportional hazards regression model adjusted for proliferative index (Ki-67), peritumoral vascular invasion, tumor size, nodal status and HER2 overexpression.
Annals of Oncology
for whom tamoxifen alone is considered reasonable treatment option. In conclusion, the present study indicates that the outcome of very young patients with early breast cancer is worse in selected tumor subtypes identified by IHC. Moreover, the results presented in this study support the hypothesis that the progress in the adjuvant treatment of very young patients requires study of tailored treatments in specific ‘niches’ of patients. It should, however, be emphasized, however, that the tumor subtypes identified in the current study still include heterogeneous groups of tumors and that the identification of further tumor subtypes amenable to targeted treatments represents a research priority.
None of the authors declare conflicts of interest.
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original article