|Year : 2018 | Volume
| Issue : 7 | Page : 1627-1631
Favorable progression-free survival in women with two different histopathological subtypes of bilateral breast cancer
Yuyi Wang1, Chi Du2, Li Tu1, Feng Luo1, Xi Yan1
1 Department of Medical Oncology, Cancer Center, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
2 Department of Oncology, The Second People's Hospital of Neijiang, Neijiang, Sichuan, China
|Date of Web Publication||19-Dec-2018|
37th Guoxue Lane, Wuhou District, Chengdu, Sichuan 610041
Source of Support: None, Conflict of Interest: None
Purpose: The aim of this study was to classify bilateral breast cancers (BBCs) into two groups according to histopathological or molecular subtypes of the two breast diseases in each patient and to study their characteristics in relation to survival outcomes.
Methods: Fifty-six BBC patients were enrolled in the study. They were classified according to whether the two breast diseases were of the same or different histopathological subtypes (defined as S-his or D-his groups) and molecular subtypes (defined as S-mole and D-mole groups). Progression-free survival (PFS), overall survival (OS), and important characteristics were then compared between the groups.
Results: We observed that the PFS and OS of the S-mole and D-mole groups failed to reach a significant difference. However, D-his BBC patients enjoyed longer PFS than their S-his counterparts, although the OS was similar. To explore the reason for the extended PFS in D-his BBC patients, we first focused on the possible prognostic contribution by various histopathological subtypes in the groups. We compared the proportion of infiltrating ductal carcinoma, infiltrating lobular carcinoma, and other breast cancer subtypes in the D-his and S-his groups, and demonstrated that they were not associated with longer PFS. We then examined age, menopausal status, tumor, node, and metastasis (TNM) stage, expressions of estrogen receptor (ER), progesterone receptor (PR) and Ki67, and metastasis to lymph nodes, viscera, and bone. The results indicated no significant between-group differences in age, TNM stage, ER/PR expression, and metastasis to viscera and bone. However, significantly lower levels of Ki67and decreased lymph node metastasis rate were associated with D-his BBC patients, which might explain the observed longer PFS.
Conclusions: In comparison to S-his, D-his BBC patients had longer PFS, which was associated with lower levels of Ki67 and a decreased lymph node metastasis rate.
Keywords: Bilateral breast cancer, histopathological subtype, molecular subtype, progression-free survival
|How to cite this article:|
Wang Y, Du C, Tu L, Luo F, Yan X. Favorable progression-free survival in women with two different histopathological subtypes of bilateral breast cancer. J Can Res Ther 2018;14:1627-31
|How to cite this URL:|
Wang Y, Du C, Tu L, Luo F, Yan X. Favorable progression-free survival in women with two different histopathological subtypes of bilateral breast cancer. J Can Res Ther [serial online] 2018 [cited 2020 Aug 11];14:1627-31. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1627/247739
| > Introduction|| |
Patients with primary breast cancer have an increased risk of developing cancer in the opposite breast, resulting in bilateral breast cancer (BBC). In the past decade, scientists have studied and published on the characteristics of BBC, including its prognostic variables. BBCs have been categorized as synchronous BBC (sBBC) or metachronous BBC (mBBC) breast cancers ,, according to the time window between the first and contralateral breast cancer development. Synchronous BBC was considered as tumors diagnosed simultaneously in both breasts. However, subsequent studies introduced an uncertain time interval between the diagnoses of the two tumors, which could vary from just 1 month  to as long as 5 years. Apart from time interval, other criteria described about three decades ago have been introduced to distinguish sBBC from mBBC. The criteria for sBBC included different histological types, a greater degree of histological differentiation, no evidence of local, regional or distant metastasis, and exclusion of Stage IIIb and IIIc (T4 or N3) tumors. However, these criteria inadvertently excluded some sBBCs, such as patients who developed BBCs that demonstrated similar histopathology.
It can be concluded from the aforementioned descriptions that there is still lack of a well-accepted standard that could be used to clearly differentiate between sBBC and mBBC. Therefore, the results of studies based on this uncertain criterion are less convincing. It might be an unsatisfactory and incorrect choice to merely divide BBCs into sBBC and mBBC. Besides, using this classification system precludes drawing clear conclusions. Therefore, a better and widely accepted classification is in need. In fact, besides the diagnostic interval between the two breast cancers, many differences could exist among BBC patients. They could be administered different treatments, and the tumors could have the same or different molecular and histological features, or tumor, node, and metastasis (TNM) stages. In addition, the two breast cancers could both develop before or one before and the other after childbirth.
For the first time, we have classified BBCs according to histological subtypes based on the World Health Organization classification of tumors (International Agency for Research on Cancer [IARC] 2003 version), and molecular subtypes using the 2013 St. Gallen consensus. We made this sorting because the histological and molecular subtypes of breast cancer is associated with treatment and prognosis. BBCs with the same histology were sorted into the same histopathological subtype (S-his) group, while the rest were grouped as the different histopathological subtype (D-his) group. Similarly, an S-mole group was defined as patients with the same molecular subtype on the basis of expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (Her2), and Ki67 in both cancers, while different gene expression patterns defined a D-mole group. This version of classification is based on generally approved standards, and therefore analyses made in line with them are convincing.
| > Methods|| |
We identified 65 patients diagnosed with BBCs in the Oncology Center of West China Hospital from 1999 to 2014 for this study (There are 9800 breast cases at the time we made the analysis and 0.66% of breast cancer patients are diagnosed as BBC). The criteria for diagnosing BBC partly followed the description of Chaudary et al., which are the demonstration of in situ disease and no evidence of local, regional, or distant metastasis. Patients who were diagnosed with Stage IV cancers in either two of the breasts were excluded, considering the possibility that metastatic disease might be the reason of BBC diagnosis. All of the included BBC cases (n = 56) were female patients with a mean age of 51.2 years. Among them, one was of Mongol nationality, one was Tibetan, and the rest were Han. The 2013 St. Gallen consensus was used as the molecular subtype classification system. The World Health Organization classification of tumors (IARC 2003 version) was used as the histopathological diagnostic criteria. The American Joint Committee on Cancer (edition 7) TNM classification system was used for staging, and the analysis was based on the more advanced tumor of the two diseases. For example, if a patient had Stage I cancer in one breast and Stage III in the other, we classified the patient as having Stage III. ER, PR, and Ki67 expressions were judged based on the higher expression data between two breast diseases, considering antihormone therapy were utilized as long as ER/PR expression on one of the two breasts was positive and relatively poorer prognosis could be predicted as long as Ki67 expression no <14% on any side of breast diseases. All patients received standard treatment following the NCCN guidelines, such as surgery, chemotherapy, and radiotherapy according to their situations. The West China Hospital of Sichuan University ethics committee approved the study protocol.
The Kaplan–Meier method was used to estimate overall survival (OS), and the log-rank statistics was used to test for differences among subgroups. Student's t-test was used to compare the age differences between the two groups. For molecular or clinicopathological characteristics, including menopausal status, ER/PR status, and TNM stage, the Chi-square test was used for analysis. Continuity correction result was used when a cell contained <5 and ≥1. Fisher's exact test was used when at least 2 cells contained <5, or 1 cell contained <1. A significant finding was defined as a P value below 0.05. All calculations were performed using IBM SPSS statistics version 22.0 (IBM Corporation, Armonk, NY, USA).
| > Results|| |
Patients with different histopathological subtype breast cancers have longer progression-free survival than same histopathological subtype cases
We first compared progression-free survival (PFS) and OS between the S-his and D-his groups, and also between the S-mole and D-mole cases. There were no statistically significant differences in PFS [Figure 1]a and OS [Figure 1]b between the S-mole and D-mole groups (P = 0.2881 and 0.1933, respectively). However, breast cancer patients with D-his had longer PFS [Figure 1]c than those with S-his (P = 0.0355) although OS [Figure 1]d was similar (P = 0.2751).
|Figure 1: Progression-free survival and overall survival according to breast cancer subtype. (a) Progression-free survival for the same molecular subtype (S-mole) and different molecular subtype (D-mole) breast cancer patients. (b) Overall survival for S-mole and D-mole breast cancer patients. (c) Progression-free survival for the same histological subtype (S-his) and different histological subtype breast cancer patients. (d) Progression-free survival for S- same histological subtype and different histological subtype breast cancer patients|
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Comparison of histopathological subtypes of breast cancers in the same histopathological subtype and different histopathological subtype groups
We discontinued further investigation of BBC based on molecular subtypes (S-mole vs. D-mole) in view of the lack of statistically significant survival differences between them. However, we attempted to unveil the reason for the longer PFS observed in the D-his group. Because breast cancer prognosis is partly dependent on histological subtypes and very different therapy method will be used among ductal carcinoma in situ, infiltrating carcinoma, including infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC), and other subtypes such as mucinous breast cancer. We first hypothesized there might be different proportions of histopathological subtypes in the D-his and S-his groups. One hundred and twelve breast cancers of 56 BBC cases were analyzed, and the result of histological subtype comparison, however, showed no statistically significant difference between the groups (P = 0.208) [Table 1].
|Table 1: Comparison of clinicopathological characteristics between the bilateral breast cancer with the same histopathological subtypes and the different histopathological subtype|
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Comparison of clinicopathological and molecular features of same histopathological subtype and different histopathological subtype bilateral breast cancers
We have excluded that longer PFS in D-his group is related to histopathological subtype. In further exploration, we compared age, menopausal status, TNM stage, and ER, PR, Her2, and Ki67 expression between the S-his and D-his subgroups. No statistically significant difference in age (P = 0.1914), menopausal status (P = 0.143), TNM stage (P = 0.342), and ER/PR expression (P = 1.000) was observed between the groups. However, the number of cases in the S-his group with expression of ki67 ≥14% was statistically greater than in the D-his group (P = 0.034). The expression intensity of Her2 in pathological slices was categorized as negative(-), weak-positive (+), moderate-positive (++), and strong-positive (+++). Negative and weak-positive expressions were considered Her2-negative cases, while strong-positive expression was classified as Her2 positive. As for moderate-positive expression, Her2/chromosome enumeration probe 17 fluorescence in situ hybridization is required for categorization. There was no significant difference in Her2 expression between the S-his and D-his groups (P = 0.518) [Table 1].
Metastasis occurrence in same histopathological subtype and different histopathological subtype groups at follow-up
The metastasis to lymph nodes (these are not the lymph node metastasis observed when BBC was diagnosed), viscera and bone were analyzed, and the difference between S-his and D-his groups compared. The result indicated a significantly higher incidence of lymph node metastasis in the S-his than the D-his group (P = 0.011). However, metastases to viscera (P = 0.625) and bone (P = 0.155) were similar in S-his and D-his BBC cases.[Table 1].
| > Discussion|| |
We classified BBC patients into either S-his and D-his groups or S-mole and D-mole groups, instead of sBBC and mBBC, as many published studies have done (In fact, we also analyzed BBC patients by dividing them into the synchronous and metachronous cases. Among them 15 cases are synchronous BBC, and 8 cases are S-his and 7 cases are D-his. The results suggest that two breast cancers of synchronous BBC do not tend to be the same histological subtype). Our classification method is based on a clear and well-accepted classification criterion. In addition, there are prognostic and treatment differences between different histological and molecular subtypes of breast cancer.,
It is notable that no recommended treatment guidelines for BBC have been established. With respect to surgery, one study reported that patients with BBC could be safely treated with bilateral breast conservation, and the cosmetic outcome was comparable to patients who underwent unilateral breast conservation. With respect to adjuvant chemotherapy and radiotherapy or chemotherapy and radiotherapy for those not suitable for surgery, the most commonly accepted approach is to choose therapeutic regimen according to the most adverse histological characteristics of the two tumors.,,, Imatinib, inhibitor of c-kit, was also reported effective in the treatment of an c-kit-positive expression BBC case. However, there are no studies and data to support the validity of this approach. In recent decades, molecular subtyping has been introduced for individualized disease management. Breast cancer subtypes include luminal A, luminal B (further divided into luminal B Her2 negative and luminal B Her2 positive), Her2 positive, and basal-like(triple negative) according to expression of ER, PR, Her2, and Ki67. The subtypes are tightly related to therapies and prognosis of patients. With regard to the relationship of molecular subtypes with prognosis and treatment of BBC, to the best of our knowledge, there are no reports.
In this study, we uncovered that both PFS and OS were similar between D-mole and S-mole groups, which suggests that similarities or differences in molecular subtypes between two breast cancers had no prognostic relevance. However, the finding of longer PFS in D-his than S-his BBC patients suggest BBC patients with two different histopathological subtypes have better prognosis. Our further analysis of the molecular and clinicopathological differences between D-his and S-his groups uncovered a significantly lower expression of Ki67 in association with a decreased rate of lymph node metastasis in the D-his group. These findings might explain the longer PFS in D-his BBC patients although their OS was not extended.
Ki67 is a well-known nuclear proliferation marker that is expressed in all phases of the cell cycle except G0. Because proliferation is a key process of malignant tumors, many reports have investigated its possibility as a prognostic biomarker in breast cancer.,, The widely used clinical cutoff value of Ki67 proposed is 14%. It is now well-known that Ki67 plays a prognostic role in breast cancers, and most of these evidence derived from IDC patients. Other studies have attempted to uncover the relationship between Ki67 and OS or PFS in breast cancer patients with other histopathological subtypes. One study observed survival benefits in ILC patients using a Ki67 cutoff value of 20%, but demonstrated that Ki67 was not suitable as an independent prognostic indicator. On the contrary, another study associated high levels of Ki67 with poor prognosis of ILC patients. However, there are no reported studies focused on histopathological subtypes of BBC and Ki67. For the first time, our study uncovered that BBC patients with two different histological subtype breast diseases have higher level of Ki67.
Another finding from our study was the high rate of lymph node metastasis in S-his BBC patients. Evaluating the status of axillary lymph nodes is vital in predicting the long-term survival in breast cancer , not only at the time of diagnosis but also during follow-up. Metastatic breast cancer cells will first infiltrate into nearby lymph nodes to start metastasis. Thus, lymph node metastasis is associated with poor prognosis of cancer.
The limitation of this study is the small number of BBC cases included and major explanation for it is the low incidence of BBC (Among 9800 breast cases in this report, only 56 of them are diagnosed as BBC). According to a meta-analysis which included nine studies, about 0.93% of breast cases are BBCs, and the result is similar with our discovery, 0.66%. Although we failed to observe significant difference on OS between the S-mole and the D-mole groups, the OS curves tend to be different [Figure 1]b. They may disclose a difference when the number of cases increases.
| > Conclusions|| |
For the first time, our study classified BBC cases into two groups according to whether the histopathological subtypes of each patient's two breast cancers were the same (S-his) or different (D-his). We discovered D-his BBC patients enjoy longer PFS and further study indicated that the better prognosis was related to lower levels of Ki67 and a decreased rate of lymph node metastasis. Further studies might be needed to explain this phenomenon and the result concluded at present can be used for prognosis of BBC patients.
Compliance with ethical standards
The West China Hospital of Sichuan University ethics committee approved the study protocol.
Financial support and sponsorship
This work was supported by Sichuan Society of Medicine, The Youth Medical Research Creative Project (Q16042) (grantee: Chi Du).
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Schwentner L, Wolters R, Wischnewsky M, Kreienberg R, Wöckel A. Survival of patients with bilateral versus unilateral breast cancer and impact of guideline adherent adjuvant treatment: A multi-centre cohort study of 5292 patients. Breast 2012;21:171-7.
Kollias J, Ellis IO, Elston CW, Blamey RW. Prognostic significance of synchronous and metachronous bilateral breast cancer. World J Surg 2001;25:1117-24.
Carmichael AR, Bendall S, Lockerbie L, Prescott R, Bates T. The long-term outcome of synchronous bilateral breast cancer is worse than metachronous or unilateral tumours. Eur J Surg Oncol 2002;28:388-91.
Uglyanitsa KN, Nefyodov LI, Brzosko V. The incidence of cancer in the second breast: After radicalremoval of one breast for cancer. JAMA 2000;77:454-7.
Abdalla I, Thisted RA, Heimann R. The impact of contralateral breast cancer on the outcome of breast cancer patients treated by mastectomy. Cancer J 2000;6:266-72.
Bloom ND, Daluvoy RV, Ceccarelli F, Degenshein GA. Bilateral mammary carcinoma; immunologic implications. N Y State J Med 1980;80:908-10.
Chaudary MA, Millis RR, Hoskins EO, Halder M, Bulbrook RD, Cuzick J, et al.
Bilateral primary breast cancer: A prospective study of disease incidence. Br J Surg 1984;71:711-4.
Jung SP, Lee SK, Kim S, Choi MY, Bae SY, Kim J, et al.
Invasive pleomorphic lobular carcinoma of the breast: Clinicopathologic characteristics and prognosis compared with invasive ductal carcinoma. J Breast Cancer 2012;15:313-9.
Tang LC, Jin X, Yang HY, He M, Chang H, Shao ZM, et al.
Luminal B subtype: A key factor for the worse prognosis of young breast cancer patients in China. BMC Cancer 2015;15:201.
Gollamudi SV, Gelman RS, Peiro G, Schneider LJ, Schnitt SJ, Recht A, et al.
Breast-conserving therapy for stage I-II synchronous bilateral breast carcinoma. Cancer 1997;79:1362-9.
Renz DM, Böttcher J, Baltzer PA, Dietzel M, Vag T, Gajda M, et al.
The contralateral synchronous breast carcinoma: A comparison of histology, localization, and magnetic resonance imaging characteristics with the primary index cancer. Breast Cancer Res Treat 2010;120:449-59.
Ursaru M, Jari I, Gheorghe L, Naum AG, Scripcariu V, Negru D, et al.
Bilateral breast cancer: Diagnosis and prognosis. Rev Med Chir Soc Med Nat Iasi 2016;120:316-20.
Chandrika, Permi HS, Kishan Prasad HL, Mohan R, Shetty KJ, Patil C, et al.
Synchronous bilateral medullary carcinoma of breast: Is it metastasis or second primary? J Cancer Res Ther 2012;8:129-31.
Bajpai J, Punatar SB, Gupta A, Badwe R, Gupta S. Bilateral adenomyoepithelioma of breast. J Cancer Res Ther 2013;9:523-5.
Lopez F, Belloc F, Lacombe F, Dumain P, Reiffers J, Bernard P, et al.
Modalities of synthesis of ki67 antigen during the stimulation of lymphocytes. Cytometry 1991;12:42-9.
Viale G, Giobbie-Hurder A, Regan MM, Coates AS, Mastropasqua MG, Dell'Orto P, et al.
Prognostic and predictive value of centrally reviewed ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: Results from breast international group trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 2008;26:5569-75.
Kilickap S, Kaya Y, Yucel B, Tuncer E, Babacan NA, Elagoz S, et al.
Higher ki67 expression is associates with unfavorable prognostic factors and shorter survival in breast cancer. Asian Pac J Cancer Prev 2014;15:1381-5.
Tanriverdi O, Meydan N, Barutca S. Reconsideration of clinical and histopathological prognostic factors in breast cancer patients: A single center experience. Asian Pac J Cancer Prev 2014;15:807-12.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ, et al.
Strategies for subtypes – Dealing with the diversity of breast cancer: Highlights of the St. Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol 2011;22:1736-47.
Narbe U, Bendahl PO, Grabau D, Rydén L, Ingvar C, Fernö M, et al.
Invasive lobular carcinoma of the breast: Long-term prognostic value of ki67 and histological grade, alone and in combination with estrogen receptor. Springerplus 2014;3:70.
Carbognin L, Sperduti I, Brunelli M, Marcolini L, Nortilli R, Pilotto S, et al.
Subpopulation treatment effect pattern plot (STEPP) analysis of ki67 assay according to histology: Prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer. J Exp Clin Cancer Res 2016;35:50.
Dixon JM, Anderson TJ, Page DL, Lee D, Duffy SW. Infiltrating lobular carcinoma of the breast. Histopathology 1982;6:149-61.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM, et al.
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.
Kim JY, Seo HB, Park S, Moon JI, Lee JW, Lee NK, et al.
Early-stage invasive ductal carcinoma: Association of tumor apparent diffusion coefficient values with axillary lymph node metastasis. Eur J Radiol 2015;84:2137-43.
Shayan R, Achen MG, Stacker SA. Lymphatic vessels in cancer metastasis: Bridging the gaps. Carcinogenesis 2006;27:1729-38.
Holm M, Tjønneland A, Balslev E, Kroman N. Prognosis of synchronous bilateral breast cancer: A review and meta-analysis of observational studies. Breast Cancer Res Treat 2014;146:461-75.