Familial breast cancer. Part II: Relationships with histology, staging, steroid receptors and serum tumor markers

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1 Journal of BUON 7: 61-65, Zerbinis Medical Publications. Printed in Greece ORIGINAL ARTICLE Familial breast cancer. Part II: Relationships with histology, staging, steroid receptors and serum tumor markers I. Gavrilov 1, M. Nacheva 2, D. Tzingilev 1 1 Department of Thoracic Surgery, National Oncological Centre, Sofia; 2 Department of Medical Genetics, Medical University, Sofia, Bulgaria Summary Purpose: To identify differences in clinical characteristics, histological features, hormone receptor status, and tumor marker expression between patients with sporadic and familial breast cancer. Patients and methods: As in the previous Part I of this study, two groups of women with breast cancer were compared. The first group (group I) included 504 patients with a family history of breast cancer. The second (control) group (group II) consisted of 300 patients not reporting such a history in their relatives. The examined parameters in this report were stage and axillary lymph node involvement at the time of the initial diagnosis, treatment methods, hormone receptor status, and serum levels of the tumor markers CEA and CA The data were processed and analysed using the SPSS statistical package. The statistical significance of differences between groups and subgroups was evaluated by x 2 Pearson s test and Student s paired t-test. Results: Compared to sporadic cases, patients with familial breast cancer were more often diagnosed at an advanced III or IV stage; metastatic involvement of the regional lymph nodes was more frequent in group I patients. In the same group more radical surgical procedures combined with chemotherapy and local irradiation were performed. In group I the percentage of negative hormone receptors was higher (35.3% versus 22.6%; p <0.0001) for estrogen receptors (ER), and 47.6% versus 32.6% (p <0.0001) for progesterone receptors (PR). Also, in group I raised serum levels of CA 15.3 were significantly more frequent compared with group II (48% versus 35.5%, p <0.0789), and this applied also for CEA values above 50 ng/ml (10.6% versus 1.5%, p <0.0002). Conclusion: Familial breast cancer displays particular clinical characteristics, distinguishing it from the sporadic type of the disease. Patients with familial breast cancer are usually diagnosed at an advanced stage. Commonly, the hormone receptors are negative and the serum concentrations of tumor markers elevated. The steroid receptor status represents the most reliable predictor of response to hormonotherapy and an important prognostic factor of the patient s outcome. As a result of their particular characteristics, these patients require more radical surgical techniques combined with pre- or postoperative local radiotherapy and systemic chemotherapy. Key words: estrogen receptors, familial breast cancer, progesterone receptors, prognostic factors, sporadic breast cancer, tumor markers Introduction Received ; Accepted Author and address for correspondence: Ivan Gavrilov, MD, PhD Department of Thoracic Surgery National Oncological Centre 6 Plovdivsko pole Street Sofia 1156 Bulgaria Fax: nacheva@techno-link.com In the previous Part I of our study [1] we have suggested that patients with familial breast cancer might be classified as a distinguishable group with particular reproductive features and different clinical characteristics regarding the onset, course, and outcome of the disease. When compared with sporadic cases, patients with familial predisposition to breast cancer are diagnosed in a more advanced disease stage and the tumor is more often bilateral. These patients give a history of higher

2 62 numbers of abortions. They also have an earlier age at menarche and a later age at first pregnancy. They have never nursed or reported a duration of lactation of less than one month. In Part II of this study, we further analysed parameters related to histology, hormone receptors status, serum tumor markers, and treatment methods applied. Patients and methods We reviewed the records of 804 patients with breast cancer admitted in the Thoracic Clinic of the Bulgarian National Oncological Centre between 1982 and It is the same patient population as described in detail in Part I of our study [1]. Five-hundred four out of 804 cases (group I) had a family history of breast cancer. The remaining 300 patients with the sporadic form of the disease comprised the control group (group II). Data on staging, steroid receptors, serum concentrations of CA 15.3 and CEA, type of operation and adjuvant treatment were collected from all patients. The ER and PR were determined by radioligand techniques or enzyme immunoassays on tumor cytosol preparations. Serum levels of CEA were estimated in 341 group I and in 260 group II patients, while CA 15.3 levels were measured in 302 group I and in 248 group II patients. Both markers were measured pre- and postoperatively by radioimmunologic assays using commercially available kits (Mallinckrodt, Holland for CEA, and Cys Bio International, France for CA 15.3). The upper normal serum values of CEA were 5 ng/ml in non-smokers and 10 ng/ml in smokers. The upper normal limit of CA 15.3 was 35 U/ml. For comparative analyses of the data in both groups the SPSS statistical package was used. The statistical significance of differences between groups and subgroups was evaluated by x 2 Pearson s test and Student s paired t-test. Results Table 1 shows the distribution of group I (cases) and II (controls) patients according to the surgical technique performed. Conservative surgical procedures were practically equal in both groups (7.7% versus 6.7% in groups I and II, respectively; p > 0.05), in contrast with more radical operations which were significantly more common in group I. The distribution of the cases and controls by clinical stage is shown in Table 2. The percentage of group II patients with stage I was twice as high, compared with group I patients. The proportion of stage II patients Table 1. Types of surgical treatment in groups I (cases) and II (controls) Type of surgery Group I Group II p value Quadrantectomy with 39 (7.7) 20 (6.7) NS lymph-node dissection Patay-Pirogov 13 (2.6) Patay 260 (51.6) 201 (67.0) < Patay with parasternal 118 (23.4) 57 (19.0) NS nodal biopsy Halsted 74 (14.7) 22 (7.3) < p(x 2 )=0.003 Table 2. Clinical TNM stage of the cases (group I) and controls (group II) TNM stage Group I Group II p value I 56 (11.1) 62 (20.7) <0.001 IIA 147 (29.1) 88 (29.3) NS IIB 127 (25.2) 85 (28.3) NS IIIA 21 (4.2) 8 (2.7) NS IIIB 122 (24.2) 48 (16.0) <0.001 IV 31 (6.2) 9 (3.0) <0.05 p(x 2 )= in both groups was equal. A significantly higher percentage of group I patients had had an advanced IIIB (24.2% versus 16.0%, respectively; p <0.001) or IV stage (6.2 versus 3.0%, respectively; p <0.05). Table 3 demonstrates the pathological TNM classification of the cases (group I) and controls (group II). There was a significant excess of pt1 (p=0.0006), pn0 (p=0.0001) and pm ( ) (p=0.0224) cases in the control group. The histological types and grading of breast cancer in both groups are analysed in Table 4. The noninvasive types did not differ significantly between patients with familial and sporadic breast cancer. On the contrary, invasive lobular carcinomas were significantly more common among familially predisposed patients (p <0.0398). Well-differentiated (G1) tumors were significantly less frequently seen in group I patients (14.7% versus 30.6%, respectively; p <0.0001), while cancers with poor differentiation (G3) were significantly more frequent in patients with hereditary breast cancer (46.0% versus 29.0%, respectively; p <0.0001). Table 5 describes treatment modalities other than surgery, performed in both groups. Compared to controls,

3 63 Table 3. Pathological TNM stage of the cases (group I) and controls (group II) Pathological TNM Group I Group II p value T* T1a 8 (1.6) 4 (1.3) NS T1b 13 (2.6) 32 (10.7) < T1c 74 (14.7) 54 (18.0) NS T2 286 (56.7) 163 (54.3) NS T3 95 (18.8) 25 (8.4) < T4b 28 (5.6) 22 (7.3) NS N N0 194 (38.5) 158 (52.7) < N1a 28 (5.6) N1b 163 (32.3) 106 (35.3) NS N2 95 (18.8) 29 (9.7) < N(+) with metastatic 24 (4.8) 7 (2.3) <0.05 parasternal lymph nodes M M( ) 470 (93.3) 291 (97.0) =0.01 M(+) 34 (6.7) 9 (3.0) =0.01 *for T p(x 2 )=0.0006; for N p(x 2 )=0.0001; for M p(x 2 )= Table 5. Complementary treatment modalities combined to surgery in cases (group I) and controls (group II) Complementary Group I Group II p value treatment Radiotherapy Preoperative 5 (1.0) 1 (0.3) NS Postoperative 333 (66.1) 184 (61.4) NS No radiotherapy 146 (29.0) 82 (27.3) NS Palliative external 20 (4.0) 33 (11.0) < beam radiotherapy Chemotherapy, antiestrogen therapy Preoperative chemo- 4 (0.8) therapy alone Postoperative chemo- 64 (12.7) 13 (4.3) < therapy alone Antiestrogen therapy 167 (33.1) 133 (44.3) < alone Pre and postoperative 77 (15.3) 48 (16.0) NS chemotherapy Postoperative chemothe- 149 (29.6) 71 (23.7) <0.05 rapy and antiestrogen therapy No treatment 43 (8.5) 35 (11.7) NS p(x 2 )< Table 4. Histological types and grade of tumors in cases (group I) and controls (group II) Group I Group II p value Histological type* Lobular carcinoma in situ 11 (2.2) Invasive lobular carcinoma 160 (31.7) 18 (6.0) < Intraductal carcinoma 28 (5.5) 18 (6.0) NS Invasive ductal carcinoma 265 (52.6) 231 (77.7) < Mucinous(colloid) carcinoma 30 (6.0) 26 (8.7) NS Other (medullary, tubular) 10 (2.0) 7 (2.3) NS Grade G1 74 (14.7) 92 (30.6) < G2 198 (39.3) 121 (40.3) NS G3 232 (46.0) 87 (29.0) < *for histology p(x 2 ) < ; for grade p(x 2 ) < an equal percentage of cases received postoperative radiotherapy as a result of their frequently advanced disease. Coupled with the higher proportion of hormonoresistant tumors in group I patients, adjuvant chemotherapy was significantly more often required in cases. In contrast, antiestrogen hormonotherapy was more frequently given in group II patients. As shown in Table 6, in this group the incidence of tumors with positive hormone receptors was higher. The rates of positive ER in cases and controls were 63.5% and 75.7%, respective- Table 6. Estrogen and progesterone receptors in cases (group I) and controls (group II) Receptor Group I Group II p value (n=498) (n=295) ER (63.5) 227 (75.7) < ER 178 (35.3) 68 (22.6) < missing 6 (1.2) 5 (1.7) NS PR (51.2) 197 (65.7) < PR 240 (47.6) 98 (32.6) < missing 2 (0.4) 5 (1.7) NS ER + plus PR (48.8) 179 (60.6) < p(x 2 )= ly (p <0.0001). In a similar pattern, the corresponding rates of positive PR were 51.2% and 65.7% (p <0.0001). The combination of both positive ER and PR was more frequently noted in group II patients (179 patients, 60.6%) than in group I patients (243 patients, 48.8%, p <0.0001). Negative ER were found in 35.3% and 22.6% in groups I and II patients, respectively (p <0.0001), while negative PR were registered in 47.6% and 32.6% of patients in groups I and II, respectively (p <0.0001). Table 7 shows the preoperative serum levels of CEA and CA The rate of normal CEA serum values was higher in controls. Inversely, a significant excess of CEA values exceeding 50 ng/ml was docu-

4 64 Table 7. Preoperative serum levels of CEA and CA 15.3 in cases (group I) and controls (group II) Tumor marker Group I Group II p value n (%) n(%) CEA* n=341 n=260 normal 134 (39.3) 128 (49.2) < >10 ng/ml 171 (50.1) 128 (49.2) NS >50 ng/ml 36 (10.6) 4 (1.5) < CA 15.3 n=302 n=242 normal 118 (39.1) 125 (51.7) < U/ml 145 (48.0) 86 (35.5) < >60 U/ml 39 (12.9) 31 (12.8) NS *for CEA p(x 2 )= ; for CA 15.3 p(x 2 )= mented in cases when compared to controls (10.6% versus 1.5%, p=0.0002). Similar correlations were found for CA Normal values of CA 15.3 below 35 U/ml were more frequent in controls than in cases (51.7% versus 39.1%, p=0.0001). The rate of increased CA 15.3 serum levels in the range of U/ml was higher in familially predisposed cases compared to sporadic controls (48% versus 35.5%, p=0.0001). Familial breast cancer cases were diagnosed at a younger age than their female relatives. The earlier onset of the disease in cases according to their degree of kinship to family members affected by breast cancer is shown in Table 8. There was a trend for earlier cancer development the closer the relatives with a history of breast cancer were. A family history of breast cancer in first, second and third-degree relatives was recorded in 37.5%, 20.5%, and 15.9% (p <0.001) of the cases who developed the disease at a more than 11 years earlier age. Discussion It has been previously reported that hereditary breast cancers (especially those related with BRCA 1 mutation carriers) differ from the sporadic form of the disease in terms of clinical, histological and biochemical characteristics, and age at diagnosis [1-5]. In this study, variations in histology, staging, hormone receptors, serum tumor markers, and treatment of the familial breast cancer patients were analysed. As opposed to patients with the sporadic type of the disease, familial breast cancer cases were diagnosed more frequently in an advanced stage and N2-3 or M+ disease. Hereditary breast cancer cases were also associated with a higher incidence of invasive lobular carcinoma and a higher tumor grade [6]. It is well known that steroids, especially estrogens, apart from their regulatory role in the growth and differentiation of the normal mammary gland, are also involved in the development and progression of breast carcinoma [6,7]. Thus, hormone receptors are among the most important prognostic factors [3,8-11]. Loman et al. and Hulka et al. have found that breast carcinomas carrying germline mutations of BRCA1 or BRCA2 genes are associated with low levels of ER and PR, and that familial breast cancer with a high content of PR might compose a distinct subgroup of hereditary carcinoma of the breast [12,13]. Our results are in agreement with the findings of these authors. Consequently, a genetic link to steroid receptor expression seems to be plausible. It is of considerable interest that, in the absence of known genetic abnormalities, the levels of the hormone receptors in breast carcinomas are higher compared to tumors with inherited mutations of specific tumor suppressor genes. Increased serum levels of CEA and CA 15.3 were more frequently noted in patients with hereditary predisposition to breast cancer. There was a strong trend of CEA increasing in serum with more advanced stage of disease. In our study 34% of group I patients had III and IV stages at diagnosis and all of them were found with increased serum CEA and CA 15.3 levels. Similar results have been reported by other investigators [2,14-20]. In Table 8. Age at the onset of the disease in group I cases according to the degree of kinship to family members previously affected by breast cancer Family history of breast cancer Earlier disease in 1st-degree in 2nd-degree p value in 2nd-degree in 3rd-degree p value in 1st-degree 3rd-degree p value onset in group I relatives relatives relatives relatives relatives relatives cases (years) (28.4) 20 (24.1) < (24.1) 23 (18.9) NS 85 (28.4) 23 (18.9) < (20.7) 31 (37.3) NS 31 (37.3) 33 (27.0) = (20.7) 33 (27.0) NS > (37.5) 17 (20.5) < (20.5) 36 (29.5) = (37.5) 36 (29.5) =0.06 same age or older 40 (13.4) 15 (18.1) < (18.1) 30 (24.6) NS 40 (13.4) 30 (24.6) < Total

5 65 accordance with the CEA increment seen in patients with bone or visceral metastases, we found that increased tumor marker values were associated with a poor prognosis. A panel of tumors markers, including CEA and CA 15.3, is a useful means to determine the appropriate surgical procedure and to monitor the course of the disease [6-8,19-22]. As already mentioned, patients with familial breast cancer are more often diagnosed at an advanced III or IV stage with the regional lymph nodes affected over 3 in number or in packs. This event, coupled with their other particular characteristics in terms of steroid receptor and tumor marker status, imposes on a certain treatment management and follow-up of the patients. In fact, more radical surgical techniques and more aggressive pre or postoperative treatment programs were required in these cases. In this study, analyses of the familial breast cancer patient characteristics according to the degree of kinship revealed interesting results. The incidence of invasive lobular carcinomas and high-grade tumors was higher among patients with a history of breast cancer in their first-degree relatives. In the same subgroup of cases, the rate of metastatic stage IV disease was 2 or 4-fold in patients reporting such a family history in second or third-degree relatives, respectively. Identical histology with the first-degree relatives was seen in 46.8% of the cases. The corresponding figure for patients with a positive family history in seconddegree relatives was 27.7%. In a considerable degree, group I patients developed their disease at an earlier age than did their relatives, and this was related to the degree of kinship: earlier than 11 years 37.5% of patients with a first-degree relative; 20.5% of patients with a second-degree relative; and 15.9% of patients with a third-degree relative. All of the above results indicate a more aggressive disease for patients having a first-degree relative affected by breast cancer and most likely this is related with inherited germline mutations in specific tumor suppressor genes. Acknowledgements We wish to thank Prof. Sh. Danon from the National Oncological Centre for his statistical assistance and all the colleagues for their moral support and comments. References 1. Gavrilov I, Nacheva M, Tzingilev D. Familial breast cancer. Part I: clinical studies; combined effect of family history, age and reproductive factors on breast cancer development. J BUON 2001; 6: Jager W, Kramer S, Palapelas V et al. Breast cancer and clinical utility of CA Scand J Clin Lab Invest 1995; 55: Mansour EG, Ravdin PM, Dressler LI. Prognostic factors in early breast carcinoma. Cancer 1994; 74: Lakhani SR, Jacquemier J, Sloane JP et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. 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