1Department of Medicine, 2Division of Epidemiology and Biostatistics, 3Division of Pathology, and University of Milan School of Medicine, 4Division of Senology, 5Division of Radiotherapy, European Institute of Oncology, Milan, Italy
Received 2 May 2001; revised 31 July 2001; accepted 24 August 2001.
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Abstract |
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Breast cancer rarely occurs in young women. Our knowledge about disease presentation, prognosis and treatment effects are largely dependent upon older series.
Materials and methods
We evaluated biological features and stage at presentation for 1427 consecutive premenopausal patients aged 50 years with first diagnosis of invasive breast cancer referred to surgery at the European Institute of Oncology from April 1997 to August 2000. A total of 185 patients (13%) were aged <35 years (very young) and 1242 (87%) were aged 3550 years (less young). The expression of estrogen receptors (ER), progesterone receptors (PgR), presence of vascular invasion (VI), grading (G), expression of Ki-67, HER2/neu overexpression, pathological stage according to TNM staging system (pTNM), pathological tumor size and number of axillary lymph node involvement were evaluated.
Results
Compared with less young patients, the very young patient group had a higher percentage of tumors classified as ER negative (P <0.001), PgR negative (P = 0.001), higher expression of Ki-67 20% of cells stained; 62.2% versus 53%, (P <0.001), vascular or lymphatic invasion (48.6% versus 37.3%, P = 0.006), and pathological grade 3 (P <0.0001). There was no difference between the two groups for pT, pathological tumor size (pN) and number of positive lymph nodes.
Conclusions
We conclude that compared with less young premenopausal patients, very young women have a greater chance of having an endocrine-unresponsive tumor, and are more likely to present with a higher grade, more extensively proliferating and vessel invading disease. Pathological tumor size, nodal status and number of positive axillary lymph-nodes have a similar distribution among the younger and the older cohorts, thus not supporting previous data indicating more advanced disease in younger patients at diagnosis of operable disease.
Key words: breast cancer, prognostic features, very young women
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Introduction |
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Patients and methods |
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Statistical analysis
The aim of this analysis was to compare tumor characteristics and biological markers in two groups of patients: the very young, aged <35 years, and the less young, aged between 35 and 50 years. Several items among the main prognostic features were incomplete in some of the patients. Some of these were subsequently retrieved. Grading was not provided by pathologists in the group of patients submitted to preoperative chemotherapy due to the interference of treatment with the architectural and cytological features of the tumors not allowing a reproducible classification. Moreover, staining for HER2/neu overexpression was carried out on a routine basis only starting from September 1999.
ER, PgR and Ki-67 were categorized into their clinically accepted groups. There are no clinically relevant categories for HER2/neu, which was split into two groups at the 10% level. The associations between the categorical variables and age group were measured in contingency tables using two sided 2 tests of association. Furthermore, we used the MannWhitney U-test to investigate whether the median values of the quantitative biological variables were associated with age. A first analysis included all the eligible patients. A second analysis excluded patients treated with preoperative chemotherapy (211 patients).
An analysis was also conducted by dividing the population in to four age groups (<35, 3540, 4145 and 4650 years). In this case, the linear by linear interaction test was used to assess the association between the four age groups and then they were ordered in categories based on tumor size, and the presence or absence of lymph node metastases and their number. This test was also used to evaluate the association among the tumor biological characteristics. The KruskalWallis test was used for the quantitative biological markers. We performed a binary logistic and multinomial regression analysis to estimate the interdependence between the tumor characteristics, biological features (both as categorical and continuous variables) and age.
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Results |
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Similar results were observed when analyzing the groups without the inclusion of patients who had pre-operative chemo-therapy (1211 patients: very young 145, less young 1066). Compared with the less young group there was a higher percentage of patients with tumor characteristics thought to be associated with dire prognosis in the very young group: ER negative (35.9% versus 20.3%, P <0.001), PgR negative (45% versus 32.4%, P = 0.004), Ki-67 20 (73.8% versus 57.2%, P <0.001), VI present (44.8% versus 35.4%, P = 0.045), grade 3 (61.5% versus 37.4%, P <0.001). The overexpression of HER2/neu (43.2% versus 36.8%, P = 0.412) was not different in the two groups.
According to the predefined age groups (<35, 3540, 4145 and 4650 years) there was strong evidence of age gradients with regard to what we considered features associated with dire prognosis: ER negative, PgR negative, Ki-67 20%, presence of VI, high grade (grade 3) and overexpression of HER2/neu (Figure 1). Most strikingly the percentage of patients with ER-positive disease increased with increasing age.
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In the logistic and multinomial regression analysis we investigated the independent association of age with the biological features using the quantitative values. Ki-67, VI, PgR and ER were all associated with age, but in view of the high correlation between ER and PgR, the level of ER did not have an independent effect after considering the association between age and PgR. An ER-positive tumor is associated with patients aged 3550, but the percentage of ER-positive cells is not. In contrast, a PgR-positive tumor is not associated with age, adjusting for ER positivity, but if over 75% of the tumor cells are PgR positive then this is associated with patients aged 3550. If we further include the effect of grade, Ki-67 is not independently associated with age in addition to the association between grade and age. Grade, ER positivity, PgR and VI all had independent associations with age. We conclude that the association between Ki-67 and age is not independent of the association between grade and age. In fact, Ki-67 is known to be a surrogate indicator to grading [16].
Table 2 shows the characteristics of stage at presentation for very young patients as opposed to the less young group. No statistically significant difference was observed for stage of disease at diagnosis [according to the TNM (tumournodemetastasis)] [17], for pathological tumor size and for the number of nodes involved. In fact, T1 was registered in 48% and 57% of the patients in the two groups, respectively. Tumors <1 cm in diameter were found in 15% and 13%. Similarly, node negative disease was recorded in 30% of the cases in both groups, 32% and 30% had one to three nodes involved and 10% had 10 nodes in both groups. No trends with age were observed for pathological stage according to TNM (pTNM), tumor size and degree of axillary node involvement when analyzing the data according to the predefined age groups (<35, 3540, 4145 and 4650) (Figure 2).
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Discussion |
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Data from past series include information on several aspects of the disease collected in an earlier period, when neither systemic treatments nor various prognostic and predictive factors were available in the way they are today [19]. Adjuvant systemic therapies, increased attention to axillary lymph node involvement and determination of the degree of expression of steroid hormone receptors are probably the most relevant variations of features between current and past assessments.
Two important findings are related to responsiveness to endocrine therapy in very young patients with breast cancer. The first relates to the observation in the current series that very young patients had tumors with less immunoreactivity for ER and PgR than older premenopausal patients. Reliable information on large cohorts of patients with data on ER and PgR are rare, and usually receptor determination based on ligand-binding assay (LBA) is reported. This method of determination, directed towards the steroid hormone binding domain, is influenced by endogenous estrogens and progesterone much more so than immunohistochemical staining [20]. The relevance of immunohistochemical evaluation for prediction of response to endocrine treatment was recently reported, with the conclusion that immunohistochemical evaluation is superior to the LBA for predicting prognosis of patients who were treated with adjuvant endocrine therapy [21]. Response to endocrine therapy was postulated even when tumors expressed as few as 1% of immunohistochemically stained cells.
The second finding relates to the reduced efficacy of adjuvant chemotherapy for very young patients with endocrine responsive tumors compared with less young premenopausal women. It is well known that chemotherapy exerts some of its effect via an endocrine mechanism in premenopausal women with ER-positive tumors, as recently published [18]. The International Breast Cancer Study Group (IBCSG) assessed the course of the disease in 3700 pre- and perimenopausal patients treated in various trials of timing and duration adjuvant systemic therapy containing cyclophosphamide, methotrexate and fluorouracil (classical CMF) [22]. Three hundred and fourteen of these women were <35 years old at trial entry. Younger patients with ER-positive tumors had a significantly worse prognosis than younger patients with ER- negative tumors [10 year disease-free survival (DFS) 25% versus 47%, hazard ratio (HR) 1.49, P = 0.014]. The largest difference in 10-year DFS between younger and older women was observed for those with ER-positive tumors who did not achieve amenorrhea compared with those who had some cessation of menses [23% ± 6 versus 38% ± 3; HR 1.67; 95% confidence interval (CI) 1.192.34; P = 0.003]. This retrospective analysis on treatment outcome leads to the hypothesis that the endocrine effects of chemotherapy alone were insufficient for patients in the younger age group with endocrine-responsive tumors, for whom suppression of estradiol production might be essential.
The results of our study, based upon an analysis of patients referred to a single center, clearly indicate that very young patients presented more frequently tumors with high grade, PVI and high proliferating fraction than less young premeno-pausal patients. Despite the fact that high grade is a controversial prognostic marker for invasive breast carcinoma [2325], it is frequently used in the decision making process for offering adjuvant treatments, and its role within this context was recently specified [26].
A component for integration of histological grade is related to mitosis. Mitotic index was in fact shown to carry autonomously prognostic relevance [27]. Ki-67 staining might provide a more accurate figure than mitotic counts [16, 28, 29]. Also, VI was demonstrated to correlate with prognosis [3032]. These features are all known to be related to baseline prognosis, but no data are available for very young patients.
The distributions of percentages of tumors with overexpression of HER2/neu in the two cohorts of very young and less young premenopausal women were similar. Others published results, based on small groups of patients, dismiss the association between age and overexpression of c-erbB-2 [33]. The observation of this feature in invasive breast cancer is considered a relevant factor for dire prognosis [3437]. However, although preliminary owing to the limited number of evaluable patients, our observation does not support the role of this specific feature as a marker for biological aggressiveness of the disease in very young patients with operable breast cancer.
Women diagnosed with breast cancer at the age of <35 years are likely to have germ-line BRCA1 or BRCA2 mutations in up to 1530% of cases [3840]. These mutations are more frequently associated with higher histological grade, lack of ERs and high proliferation rate. It might be hypothesized that germ-line mutations could partially explain the more aggressive breast cancer in young patients. Information is scarce on the efficacy of endocrine therapies (tamoxifen, ovarian suppression or a combination of both) or of the cytotoxics with respect to the presence of BRCA1 and BRCA2 mutations. Focused investigations might allow improvement of treatment indications, which cannot be otherwise extrapolated from trials on an older population.
The Experts Consensus of the St Gallen Conference 1998 indicated age <35 to be a dire prognostic variable [41], while there has been a clear advancement throughout focusing on tailored treatments according to endocrine responsiveness (St Gallen 2001). The results of the present study indicate that very young patients presented more frequently tumors with poor prognostic features such as high grade, PVI and high proliferating fraction than less young premenopausal patients. Although data on prognosis and treatment outcomes are not available for the current series mainly due to the short follow-up, the observed results indicate that a large group of very young patients presents with endocrine responsive disease and therefore might enjoy the effect of tailored endocrine systemic therapies. On the other hand, endocrine therapies are not easy to offer to very young patients [4246], and further investigations in this specific field are urgently needed [47].
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Footnotes |
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