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Bilateral Breast Cancer After Multimodality Treatment: A Report of Clinical Outcomes in an Asian Population
Accepted Manuscript Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population Tabassum Wadasadawala, Shirley Lewis, Vani Parmar, Ashwini Budrukkar, Sudeep Gupta, Nita Nair, Tanuja Shet, Rajendra Badwe, Rajiv Sarin PII:
S1526-8209(17)30383-X
DOI:
10.1016/j.clbc.2017.11.003
Reference:
CLBC 710
To appear in:
Clinical Breast Cancer
Received Date: 19 June 2017 Revised Date:
3 October 2017
Accepted Date: 2 November 2017
Please cite this article as: Wadasadawala T, Lewis S, Parmar V, Budrukkar A, Gupta S, Nair N, Shet T, Badwe R, Sarin R, Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.11.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population. 1*
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Tabassum Wadasadawala , Shirley Lewis , Vani Parmar , Ashwini Budrukkar , Sudeep Gupta , Nita Nair , Tanuja 5
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Shet , Rajendra Badwe , Rajiv Sarin
1 Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Mumbai
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2 Department of Radiation Oncology, Tata Memorial Centre, Mumbai. 3 Department of Surgical Oncology, Tata Memorial Centre, Mumbai. 4 Department of Medical Oncology, Tata Memorial Centre, Mumbai. 5 Department of Pathology, Tata Memorial Centre, Mumbai.
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Abstract:
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Purpose: Bilateral breast cancer (BBC) is an uncommon presentation. The characteristics and outcomes of synchronous and metachronous BBC were compared within an Indian cohort. Methods: This is a retrospective audit of 193 BBC patients treated at a tertiary hospital in India over a period of 10 years from January 2004 to December 2014.The demographic, tumour and treatment characteristics was compared between synchronous (N=131) and metachronous tumours (62 patients) using descriptive analysis. The survival outcomes were assessed using Kaplan Meier survival curves and compared using log rank test. Univariate and multivariate analysis was done using cox proportional hazards model to assess the impact of the prognostic factors on survival.
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Results: The mean age of presentation in synchronous (SBBC) and metachronous (MBBC) was 55 years (standard deviation (SD): 12.5) and 51 years (SD: 9.5) respectively. The median time to contralateral presentation in MBBC was 3.8 years. Mean tumour size was higher in SBBC (p 0.01). BRCA mutation was positive in 13/38 evaluated patients (of which 12 patients with MBBC). The concordance rates for the estrogen (ER) and progesterone (PR) receptor negativity and triple negative receptor status were higher in MBBC compared to SBBC (p<0.001). Grade III tumour was more frequently seen in MBBC (p=0.03).The median follow up of the entire cohort was 42 months (range 30-60 months): 45 months for SBBC and 35 months for MBBC. The 3 year rates of overall survival (OS), disease free survival (DFS) and locoregional control (LRC) for SBBC and MBBC was 88% and 90%, 74% and 64% and90% and 84%respectively. There was no difference in overall OS, DFS and LRC between SBBC and MBBC.
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Conclusion: Bilateral breast cancer is an uncommon presentation. Synchronous presentation was commoner. Metachronous tumours differ from synchronous with higher grade of presentation and less expression of ER. There was no difference in outcome between synchronous and metachronous tumours. Key words: Bilateral, breast cancer, synchronous, metachronous, survival. Type of manuscript: Original Scientific Article. Running title: Outcomes of Bilateral breast cancer. *Address for Correspondence Dr Tabassum Wadasadawala. Associate Professor, ACTREC, Tata Memorial Centre
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Mumbai - 410210 Email ID: [email protected], [email protected]
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Phone: +91-22-27405079
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Title: Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population.
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Abstract: Purpose: Bilateral breast cancer (BBC) is an uncommon presentation. The characteristics and outcomes of synchronous and metachronous BBC were compared within an Indian cohort. Methods: This is a retrospective audit of 193 BBC patients treated at a tertiary hospital in India from January 2004 to December 2014. The demographic, tumour, treatment characteristics and survival outcomes was compared between synchronous (SBBC)(N=131) and metachronous (MBBC)(62 patients).
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Results: The mean age of presentation in SBBC and MBBC was 55 years ( (SD): 12.5) and 51 years (SD: 9.5) respectively. The median time to contralateral presentation in MBBC was 3.8 years. Mean tumour size was higher in SBBC (p 0.01). BRCA mutation was positive in 13/38 evaluated patients. The concordance rates for the estrogen (ER) and progesterone (PR) receptor negativity and triple negative receptor status were higher in MBBC compared to SBBC (p<0.001). Grade III tumour was more frequently seen in MBBC (p=0.03).The median follow up of the entire cohort was 42 months (range 3060 months). The 3 year rates of overall survival (OS), disease free survival (DFS) and locoregional control (LRC) for SBBC and MBBC was 88% and 90%, 74% and 64% and 90% and 84% respectively. There was no difference in overall OS (p=0.76), DFS (p=0.13) and LRC (p=0.2) between SBBC and MBBC. Conclusion: Synchronous presentation was commoner. Metachronous tumours differ from synchronous with higher grade of presentation and less expression of ER. There was no difference in outcome between synchronous and metachronous tumours.
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Key words: Bilateral, breast cancer, synchronous, metachronous, survival.
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Introduction Breast cancer is the most common cancer among women worldwide and the second most common cause of mortality.[1] Bilaterality is an uncommon presentation and its incidence is about 3-5%.[2,3]The incidence of bilateral breast cancer (BBC) seems to have increased due to improved survival rates after treatment and early detection during follow up with surveillance mammography.[4,5] Various risk factors have been associated with BBC, the most common being lobular histology, hereditary cancers, young age at presentation and positive BRCA mutation.[6,7,8]
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BBC can be classified as synchronous or metachronous based on the time interval of presentation from the first tumour. There is wide variation in literature on the time interval used to define synchronous or metachronous BBC.[9,10,11] Three months is most commonly accepted and described in various large cohort studies.[12] The incidence of synchronous BBC (SBBC) and metachronous BBC (MBBC) described in literature is 0.2-0.3% and 2-20% respectively. [13,14]
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BBC tends to fare poorer than unilateral breast cancers. A recent metaanalysis has shown that SBBC have worse prognosis than unilateral cancers.[15] However, MBBC have a better survival than synchronous.[16] The factors predicting for worse outcomes in MBBC are young age (less than 40 years), short interval to development of contralateral breast cancer (CBC), no adjuvant treatment for the index cancer, symptomatic presentation as compared to screen detected, discordance of receptor status, histology and grade. [11,17,18]
Material and Methods
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There are large institutional series reporting outcome of BBC.[11,12] However, data from Asia and Indian subcontinent is lacking and limited to small numbers.[19] The objective of this study is to present the clinicopathological characteristics, treatment and long term outcome of BBC patients treated at a tertiary care centre in India.
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This is a retrospective audit of BBC patients treated at a tertiary care hospital in India over a period of 10 years from Jan 2004 to December 2014. The data about demographics, tumour characteristics, treatment and outcome was collected from treatment charts, medical records and prospectively maintained databases.
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All patients with an initial diagnosis of invasive breast cancer were included in the study. A 6 month cut off (from the date of initial breast cancer diagnosis) was used to classify synchronous and metachronous bilateral tumors. Oligometastatic patients treated with curative intent were included. All patients received curative multimodality treatment with surgery, chemotherapy and radiation therapy as per institutional protocol. On follow up patients were evaluated biannually with physical examination and with bilateral mammography every 18 months. Males, women with metastatic presentation (at the time of first or second cancer) and patients with missing data or defaulters after diagnosis were excluded. The variables collected were demographics, family history, BRCA mutation status if available, pathological characteristics like tumour size, histology, grade, lymphovascular invasion, axillary nodal status, hormone receptor status and treatment details (surgery, radiotherapy, chemotherapy, hormone therapy and its sequencing). Age refers to the age at the time of diagnosis for first cancer. This is in line with other studies reported earlier.[11,20] Seventh edition of the American Joint Committee on Cancer classification system
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was used for the clinical and pathological staging. The pathology and hormone status was available for all patients. Based on the hormone receptor status of 2 tumours on either side, the SBBC and MBBC were categorised into groups as suggested by Baretta et al: SBBC cohort has 3 groups [concordant positive(+/+), concordant negative (-/-), and discordant (+/- and -/+)] whereas MBBC cohort has 4 groups [concordant positive (+/+), concordant negative (-/-), negative-to positive change (-/+), and positive-tonegative change (+/-)].[21] The vital status was determined through regular follow up examinations by clinicians, telephonic review and house visits.
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For SBBC with similar dates of diagnosis, larger clinical tumour was assigned index cancer for analysis. In the event of similar size, worse grade was taken as index cancer.[12] The survival was measured from the date of diagnosis of index breast cancer in SBBC and second breast cancer in MBBC, in months, until the date of death or date of censoring, 31stDecember 2016, if patients were still alive. For MBBC, survival from first breast cancer was not considered to avoid bias resulting from longer intervals between tumours.
Results
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Statistical Analysis All statistical analysis was done using SPSS version 20. The demographics and tumour characteristics were compared between index synchronous and metachronous tumours using Pearson’s Chi-squared tests for differences in proportions for categorical variables, Mann Whitney U tests for ordinal variables and t-tests for differences in means for continuous variables. Kaplan Meier curves were used to describe overall survival (OS), disease free survival (DFS) and loco-regional control (LRC). OS was defined from date of diagnosis till death or date of censoring. DFS was defined from date of diagnosis to occurrence of relapse (local regional or distant), death or date of censoring. LRC was defined from date of diagnosis till the occurrence of local or regional relapse. Log rank test was used to compare the survival between SBBC and MBBC. Univariate and multivariate analysis was done using cox proportional hazards model to assess the impact of the prognostic factors on survival. All p-values correspond to two-sided tests and values less than 0.05 were considered significant.
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Among 33,941 women diagnosed with invasive breast cancers over the 10-year period, 131 (67%) presented with SBBC and 62 (33%) were diagnosed with MBBC. Synchronous and metachronous accounted for 0.38% and 0.18% of all cases respectively. The median time to contralateral presentation in MBBC was 3.8 years (interquartile range (IQR) 2.8-7). 58% patients had contralateral presentation within 5 years. The demographic and clinical tumour details of index SBBC and MBBC are shown in Table 1. The MBBC were younger than SBBC. The mean age of presentation in SBBC and MBBC was 55 years (standard deviation (SD): 12.5) and 51 years (SD: 9.5) respectively (p=0.05). Overall only 25 patients (13%) were less than 40 year old. Higher positive family history was documented in MBBC compared to SBBC (27% vs. 12%, p=0.009). All patients were advised to consult genetic clinic due to bilaterality especially those with positive family history. However, only 38 patients of the entire cohort were seen in genetic clinic and underwent gene testing. Overall, positive BRCA mutation status was seen in only 13 patients (12 patients were MBBC) of these 38 women tested. Only 6 BRCA positive patients had positive family history. Majority of patients in both groups were postmenopausal (p=0.9). The mean clinical tumour size was larger for SBBC [5.4 cm (SD 3)] compared to MBBC [4.5 cm (SD 2), p=0.01]. In MBBC, mean clinical tumour size of the contralateral breast cancer (CBC) was 3.6 cm (SD 2). Majority of patients were in stage II and III at presentation and infiltrative ductal carcinoma (IDC) was the most common histology in
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both groups. Lobular carcinoma accounted for only 3.6% of SBBC and 1.6-3% of MBBC. Few patients were also treated for oligometastatic bone disease along with the primary with curative intent.
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The hormone receptor status is shown in Table 2. The patients with MBBC had significantly higher rates of ER and PR receptor negativity (p<0.001) as compared to SBBC. ER and PR concordant negative rates were also higher in MBBC. Among SBBC cohort, the two tumors were ER-discordant in 20 (15.3%) patients. In MBBC cohort, the ER negative-to-positive change was observed in 6 (9.5%) patients and the ER positive to-negative change was observed in 8 (13%) patients. Though Her2 status was similar between the 2 groups (about 14-15%), triple negative receptor status was higher in MBBC (p<0.001).
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Majority of patients underwent breast conservation surgery (BCS) in both the groups (p=0.56). Neoadjuvant treatment followed by surgery was the most common approach in over 70% women with SBBC whereas women with MBBC underwent upfront surgery followed by adjuvant chemotherapy and radiation therapy for both index as well as second primary (p=0.001). Three patients received neoadjuvant hormonal therapy in SBBC group. Adriamycin based chemotherapy was most commonly used whereas taxane based chemotherapy was used in about 30%. About 90% of patients received adjuvant radiotherapy. The most common dose used was 50 Gy in 25 fractions to the breast or chest walland tumor bed boost to a dose of 15 Gy in 6 fractions in cases with BCS. The use adjuvant hormone therapy was higher in SBBC owing to higher hormone receptor positivity (p=0.001).
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Table 3 shows the treatment details of the entire cohort. Table 4 shows the pathologic characteristics. Grade III tumour was more frequently seen in MBBC (p=0.03). Ductal carcinoma in situ (DCIS) and extensive intraductal component (EIC) was more frequent in SBBC. Perineural involvement was infrequent. The average number of lymph nodes dissected was 15 with overall low rates of nodal positivity in both the groups.
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The median follow up of entire cohort was 3.5 years (42 months) (IQR 2.5-5 years). The median follow up of SBBC was 4 years (45 months) (IQR 3-6 years) whereas for MBBC it was 3 years (35 months) (IQR 14). The recurrence patterns and disease status is shown in Table 5 (Supplementary material) The median time to event (local, regional or distant) was 2 years for SBBC and 1 year for MBBC. There was no difference in recurrence patterns between SBBC and MBBC (p=0.87) with distant metastases being most common. One patient in SBBC cohort developed second primary in esophagus. There was no difference in OS, DFS and loco-regional control (LRC) between SBBC and MBBC (Figure 1).The median survival (both OS and PFS) was not reached. The 3 year OS for SBBC and MBBC was 88% and 90%, 3 year DFS was 74% and 64% and 3 year LRC was 90% and 84% respectively. The Kaplan Meier estimates for 5 year OS for SBBC and MBBC was 77%, 80%, 5 year DFS was 57% and 51% and 5 year LRC was 84% and 79% respectively. On univariate analysis, the various prognostic factors affecting LRC, DFS and OS are shown in Table 6. (Supplementary material) Univariate analyses of OS for entire cohort indicated significant differences in survival in relation to tumour size (p=0.005), ER receptor status (p=0.03), PR receptor status (p=0.01), node positivity (p=0.02), ECE (p=0.005) and surgery type for index cancer (p=0.003). For SBBC, tumour size >5 cm, ER and PR negative, Her 2 positive, PNE positive and MRM surgery has inferior survival. In SBBC, ER concordant negative tumours had poor survival outcomes compared ER concordant positive and discordant tumours (Figure 2). In MBBC, lobular histology, ER discordant, LN positive and PNE positive had inferior survival but no difference of outcomes when the 4 groups for ER and PR were assessed. On multivariate analysis for entire cohort, clinical tumour size > 5 cm had worse LRC, DFS and OS. Lymphovascular invasion was significant factor affecting LRC. Among the SBBC cohort, clinical
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tumour size > 5 cm was significant for DFS and LRC and PR status for DFS. No factors were significant for OS. Among the MBBC cohort, none of the factors were significant for LRC, DFS and OS. Discussion
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In this study, we report the outcomes of patients with SBBC and MBBC who underwent multimodality treatment at our institute and assessed the prognostic factors affecting outcome. This is the largest study reporting outcomes of bilateral breast cancers from Asia. The results of this study show no difference in OS, DFS and LRC between the SBBC and MBBC groups. Tumour size more than 5 cm was a significant prognostic factor negatively affecting outcome.
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Various factors have been proposed as risk factors for BBC. Some of them are young age, positive family history, multicentricity and lobular histology.[22,23] The mean age of presentation among SBBC was 55 years. The mean age of presentation of index MBBC was 51 years. Though only 13% patients were less than 40 years, the mean age at presentation in our cohort is still lower than that seen in western counterparts. In the study by Nichol et al, the SBBC patients were older with a mean age at presentation of 68 years.[24] Alkner and Baykara et al both reported a median age at diagnosis similar to our cohort.[13,25] In contrast, Yadav et al noted a younger subgroup of patients developing MBBC with over 50% less than 45 years.[26] Hartman et al noted that BBC patients less than 50 years had 3.9 times higher risk of death. [11]
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Beckman compared risk factors between unilateral and BBC and found that BBC was associated with positive family history (p=0.02) and lobular histology (0.04).[12] Yadav et al reported that 15 year risk of CBC in patients with positive family history was 15.3% which is similar to this study.[26] Higher positive family history was noted in MBBC compared to SBBC in our cohort. Baykara et al noted higher positive family history in SBBC (16%).[25] Overall 10% of breast cancer patients carry germ line mutations in BRCA1/2 which predisposes to cancer (annual risk 2-6%).[27] BRCA mutation carriers have a high risk for CBC compared to general population (53% vs 2%).[28] In this study, BRCA positive status was seen in 13 patients of the 38 tested, with higher positivity in metachronous (12 patients) and those with positive family history. Brien et al showed 9 had mutation in 32 tested in BBC cohort.[29] In the present study, lobular carcinoma was seen in only 3% of cases (3% in SBBC and 1.5-3% in MBBC) which is in contrast to the higher incidence reported in western literature to the tune of 16-18%. [12]
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BCS was most commonly used for SBBC (over 50%) as majority underwent down staging with neoadjuvant chemotherapy. There is no consensus on recommended surgical procedure for BBC. Although, it is proposed that the surgical treatment should be on the lines of unilateral breast cancer, practice varies. Mastectomy was commonly employed in SBBC (63%) in study by Nichol et al.[24] Similarly, mastectomy was commonly used for both index and metachronous tumours and BCS employed in only 25-27% in the study reported by Alkner et al.[13] Recent study by Brien et al showed SBBC were less likely to undergo BCS compared to MBBC.[29] The reports in literature comparing outcomes of SBBC and MBBC are conflicting, with few showing equivalent outcomes like the present study [30,31,9] while others showing inferior outcomes for MBBC [11,32,33] or for SBBC.[16,34] There was no difference in survival outcomes between SBBC and MBBC in 150 patients of BBC by Baykara et al with 5 year OS of 90% in both the cohorts.[25] This is consistent with other literature.[29] Beckman et al evaluated the outcomes of BBC in Australian cohort and noted inferior 5 year OS in of 79% in MBBC 79% as compared to 88% in SBBC (p=0.01)[12]
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The median time for CBC development in MBBC was 3.8 years with majority of patients developing second primary within 5 years. Yadav et al studied the risk factors for CBC in Indian population and noted an overall incidence of 4 %. They noted a longer time to development of CBC about 6.3 years.[26] Alkner et al showed that about 42 % developed CBC within 5 years and patients with less than 3 years to CBC had impaired disease free survival particularly in young women.[13] In the present study, about 58% developed a CBC within 5 years and DFI less than 3 years to CBC had poorer disease free survival (p=0.06). Various explanations have been proposed for poor outcome with shorter interval to CBC. CBC could be metastatic spread from index tumour as similarities in terms of morphology and genetics has been noted between tumours. [35,36] These tumours represent an aggressive and resistant phenotype occurring during or shortly after adjuvant treatment.[11]
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ER positivity was low in MBBC. This is consistent with literature.[25,12,37] The treatment of primary breast cancer tends to affect the biology of the second cancer. A change in the hormone receptor status following neoadjuvant treatment or those with relapse has been reported. Discordance of hormone receptors is seen in BBC in about 20% of cases.[38,39] This has been associated with poor survival. Barett et al evaluated the impact of receptor heterogeneity on outcome in BBC. They showed that ER status had more prognostic value over PR status. In SBBC, ER discordant tumours had intermediate OS compared to ER concordant with ER negative tumours faring worst. In MBBC, ER concordant negative and ER positive to negative change patients had poorer survival outcomes.[21] This is also supported by other studies.[40] In the present study, SBBC cohort with ER concordant negative group had inferior LRC, DFS and OS. (Figure 2) Outcomes between ER concordant positive and ER discordant could not be differentiated. In MBBC, OS was inferior among ER negative tumours (p=0.04) but there was no difference in DFS and LRC. There was no difference in outcomes between the four groups for MBBC and effect of positive to negative change could not be appreciated due to very few patient numbers in each group. A hormone receptor change has therapeutic implications for use of chemotherapy and hormone therapy in both SBBC and MBBC thereby affecting outcomes.
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The strengths of this study include large sample size from a single institution from Indian population and reporting of BRCA mutation status though in small proportion of patients. There are a few limitations. The data is abstracted from patients over a span of 10 years with a short median follow up. However, majority of large cohorts have databases of patients over 30-35 years due to the rarity of presentation. Secondly, we could not estimate the mode of detection of second primary (clinically occult or not). Alkner et al showed that in patients with metachronous breast cancer, the patients who presented with symptomatic disease had larger tumours and had a higher chance of distant metastasis compared to those detected by surveillance imaging. In contrast, patients detected to have CBC on mammography were younger and had smaller tumour size.[13] Similarly, Naveen et al showed that even in synchronous BBC, 80% were clinically occult and detected on mammography, had smaller tumour size and better outcome.[19] We have not compared the outcomes of BBC (synchronous or metachronous) with unilateral breast cancer. Various studies have reported the outcomes of BBC in comparison to unilateral tumors.[24,11] Some consider outcome to be similar and few as inferior to unilateral breast cancer. Conclusion
Bilateral breast cancer is an uncommon presentation. Synchronous presentation was commoner compared to metachronous in our cohort. Metachronous tumours differ from synchronous with higher grade of presentation and less expression of ER. There was no difference in OS, DFS and LRC between
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synchronous and metachronous tumours consistent with other cohorts. Tumour size more than 5 cm was the most significant factor negatively affecting outcome and ER negative patients had the worst survival in both synchronous and metachronous cohorts. References
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35. Imyanitov EN, Suspitsin EN, Grigoriev MY, Togo A V., Kuligina ES, Belogubova E V., et al. Concordance of allelic imbalance profiles in synchronous and metachronous bilateral breast carcinomas. Int J Cancer. 2002;100(5):557–64. 36. Hemminki K, Granström C. Morphological types of breast cancer in family members and multiple primary tumours: is morphology genetically determined? Breast Cancer Res [Internet]. 2002;4(4):R7.
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37. Senkus E, Szade J, Pieczyńska B, Zaczek A, Pikiel J, Sosińska-Mielcarek K, et al. Are synchronous and metachronous bilateral breast cancers different? An immunohistochemical analysis aimed at intrinsic tumor phenotype. Int J Clin Exp Pathol. 2014;7(1):353–63.
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38. Bu-Ali H, Sohl M, Arthi K, Vijay M. Receptor Characteristics of the Second Tumor in Synchronous Versus Metachronous Breast Cancer. Am Surg. 2008;74(8):702–6. 39. Monica B, Katrina B, Mary P. Tumor marker phenotype concordance in second primary breast cancer, California, 1999–2004. Breast Cancer Res Treat. 2010;120(1):217–27. 40. Díaz R, Munárriz B, Santaballa A, Palomar L, Montalar J. Synchronous and metachronous bilateral breast cancer: a long-term single-institution experience. Med Oncol [Internet]. 2010;29(1):16–24.
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Table 1: Baseline patient demographic and clinical tumour details. Metachronous P value Second NA 0.059
NA NA
23 (37%) 5 (8%) 34 (55%) 4.5 (SD 2)
44 (33.6%) 40 (30.5%) 2 (1.5%) 72 (55%) 50 (38%) 4 (3%) 3 (2.5%)
33 (53%) 12 (19.5%) 1 (1.5%) 36 (58%) 25 (40.5%) -
37 (60%) 9 (14.5%) 11 (18%) 30 (48.5%) 20 (32%) 1 (1.5%)
124 (94.8%) 5 (3.6%) 2 (1.6%)
61 (98.5%) 1 (1.5%) -
59 (95.5%) 2 (3%) 1 (1.5%)
0.009 0.28
SC
34 (26%) 13 (10%) 84 (64%) 4.5 cm (SD 2)
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Metachronous (n=62) Index 27 (43.5%) 35 (56.5%) 17 (27.4%)
3.6 (SD 2)
0.01 0.1
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Age (years) : ≤ 50 50 -69 ≥ 70 Positive family history Menopausal status: Pre Peri Post Mean tumour size Involved quadrant: Upper outer Central Clinical stage: I II III IV NK Histology: Infiltrative ductal Infiltrative lobular Ductal carcinoma in situ
Synchronous (n=131) 46 (35%) 70 (53.5%) 15 (11.5%) 16 (12.2%)
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Characteristics
0.2
0.9
Characteristics
Synchronous (n=131) Index Second 84 (64%) 88 (67%) 47 (36%) 43 (33%)
Metachronous (n=62) Index Second 21 (34%) 20 (32%) 41 (66%) 42 (68%)
76 (58%) 35 (36.7%) 20 (15.3%)
13 (21%) 35 (56.5%) 8 (13%) 6 (9.5%) 17 (27.5%) 45 (72.5%)
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ER: Positive Negative ER: Concordant positive Concordant negative Discordant +/-/+ PR: Positive Negative PR: Concordant positive Concordant negative Discordant +/-
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Table 2: Hormone receptor status.
72 (55%) 58 (44%)
P value <0.001 <0.001
80 (61%) 51 (39%)
19 (30.5%) 43 (69.5%)
<0.001 <0.001
64 (48.9%) 42 (32.1%) 25 (19.1%)
9 (14.5%) 37 (59.7%) 7 (11.3%)
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20 (15.2%) 15 (11.5%) 96 (73.3%) 103 (78.5%) 15 (11.5%) 13 (10%)
9 (14.5%) 7 (11%) 51 (82%) 4 (6%)
Triple Negative
16 (12.2%)
26 (42%)
9 (14.5%) 49 (79%) 4 (6.5%)
<0.001
Table 3: Treatment details
Metachronous (n=62) Index Second
P value
69 (52.5%) 62 (47.5%) 0
28 (45%) 34 (55%) 0
0.56
42 (32.5%) 3 (2%) 76 (58%) 86 (65.6%)
SC
39 (63%) 11(17.7%)
29 (46.7%) 9 (14.5%)
12 (19.3%)
16 (25.8%)
-
-
23 (37%) 50 (80%)
21 (34%) 29 (46%)
NA
0.001
0.23
117 (89%) 10 (8%) 4 (3%)
58 (93.5) 3 (5) 1 (1.5)
96 (73) 35(27)
27 (43.5) 35 (56.5)
33 (34) 63 (66)
12 (44.5) 15 (55.5)
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38 (61%) 22 (36%) 2 (3%)
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52 (39.5%) 34 (26%)
66 (50.5%) 64 (48.5%) 1 (1%)
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Surgery: BCS MRM/SMAC Done but type not known Treatment Sx CT RT ± HT NACT Sx CT RT ± HT NACT/NHT Sx RT ± HT NAHT Sx RT ± HT Chemotherapy : Neoadjuvant Adjuvant Radiotherapy Yes No NK Hormone therapy Yes No HT agent Tamoxifen AI
Synchronous (n=131) Index Second
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Characteristics
0.78
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-/+ Her 2: Positive Negative Equivocal
0.001
NA
Table 4: Pathologic characteristics. Characteristics Stage 0 I II III Grade I/II
Synchronous (n=131) Index Second 13 (10%) 16 (12%) 28 (21%) 21 (16%) 38(44%) 58 (44.5%) 52 (25%) 36 (27.5%) 40 (30.5%) 42 (32%)
Metachronous (n=62) Index Second 7 (11.5%) 12 (19.5%) 12 (19%) 14 (22.5%) 26 (42%) 26 (42%) 17 (27.5%) 10 (16%) 14 (22.5%) 11 (18%)
P value 0.24
0.03
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89 (68%) 62 (47%) 29 (22%) 3 (3.3%) 12 (9%) 0.7 cm
48 (77.5%) 17 (27.5%) 8 (13%) 3 (5%) 4 (6.5%) 0.7 cm
51 (82%) 16 (26%) 10 (16%) 0 1 (1.5%) 0.8 cm
15 2 43 (33%)
15 8 55 (42%)
15 2 8 (29.6%)
16 2 13 (21%)
Table 5: Recurrence patterns and disease status.
0.09 0.07
Metachronous (n= 62) 22 (35.5%) 4 (18.2%) 4 (18.2%) 14 (63.6%) -
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Synchronous (n= 131) 45 (34.4%) 8 (17%) 6 (13.5%) 30 (67%) 1 (2.2%) 81 (62%) 20 (15%) 22 (17%) 8 (6%)
41 (66%) 11 (16%) 10 (18%) -
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Recurrence rate: Loco-regional Loco-regional + Distant Distant Second primary Status at last follow up Alive NED Alive with disease Dead due to disease Dead other cause
0.005 0.34 0.29 0.02 0.5
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91 (69.5%) 70 (53.4%) 32 (24.5%) 10 (8%) 15 (11.5%) 0.8 cm
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III DCIS + LVI + PNI + EIC + Margins (Mean) Axillary Lymph nodes (Mean) Dissected Positive Perinodal extension(PNE)
Loco-regional control (p value)
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Variable groups
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Table 6: Univariate Analysis of prognostic factors affecting outcome.
Age (Years) <40 Vs > 40 Menopausal status Premenopausal Vs Postmenopausal Clinical Tumor size <5 cm Vs > 5 cm Grade I,II Vs III
Disease free Survival (p value)
Overall survival (p value)
Overall
SBBC
MBB C
Overall
SBBC
MBBC
Overall
SBBC
MBBC
0.68
0.60
0.97
0.47
0.2
0.24
0.2
0.13
0.9
0.77
0.71
0.25
0.48
0.085
0.14
0.43
0.23
0.61
0.004
0.002
0.58
0.001
0.001
0.06
0.005
0.03
0.1
0.53
0.56
0.86
0.03
0.01
0.56
0.14
0.13
0.96
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0.55
0.61
0.34
0.86
0.001
0.06
0.6
0.001
0.12
0.2
0.39
0.49
0.49
0.83
0.85
0.9
0.65
0.08
0.10
0.47
0.05
0.09
0.29
0.24
0.31
0.46
0.9
0.7
0.6
0.98
0.96
0.73
0.87
0.96
0.68
0.9
0.7
0.86
0.82
0.9
0.64
0.71
0.93
0.62
0.009
0.001
0.7
0.07
<0.001
0.03
<0.001
0.13
NA
0.002
0.51
NA
0.002
0.07
NA
0.002
0.04
0.01
0.007
0.79
0.04
0.002
0.19
0.01
0.002
0.78
0.54
0.91
0.4
0.02
0.04
0.57
0.15
0.04
0.71
0.46
SC
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0.05
0.07
0.28
0.65
0.42
0.04
0.73
0.7
0.17
0.34
0.44
0.014
0.1
0.01
0.02
0.18
0.008
0.1
0.6
0.002
0.01
0.02
0.005
0.04
0.01
NA
NA
0.32
NA
NA
0.06
NA
NA
0.91
0.27
NA
NA
0.13
NA
NA
0.76
NA
NA
0.17
0.06
0.82
<0.001
<0.001
0.02
0.003
0.007
0.10
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Pathological N stage 0.27 Positive vs Negative PNE Present Vs Absent 0.13 Interval to second cancer < 3 years vs > 3 years Time of presentation Synchronous Metachronous Surgery MRM vs BCS
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0.82
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Histology Ductal Vs Lobular Extensive intraductal component Present Vs Absent Lympho-vascular emboli Present Vs Absent Perineural invasion Present Vs Absent Margin status Free (>2mm) Close(<2mm) ER Receptor status Positive Vs Negative ER concordant + Vs Concordant negative Vs Discordant PR Receptor status Positive Vs Negative HER 2 neu + vs. ++ vs. +++ Triple negative Yes vs. No
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Figures
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Figure 1: Kaplan Meier graph for overall survival(A), disease free survival (B) and locoregional control (C) comparing synchronous with metachronous.
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Figure 2: Kaplan Meier graph for overall survival(A), disease free survival (B) and locoregional control (C) comparing ER concordant and discordant tumours in SBBC.
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Supplementary material Table 5: Recurrence patterns and disease status. Metachronous (n= 62) 22 (35.5%) 4 (18.2%) 4 (18.2%) 14 (63.6%) -
81 (62%) 20 (15%) 22 (17%) 8 (6%)
41 (66%) 11 (16%) 10 (18%) -
SC
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Synchronous (n= 131) 45 (34.4%) 8 (17%) 6 (13.5%) 30 (67%) 1 (2.2%)
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Recurrence rate: Loco-regional Loco-regional + Distant Distant Second primary Status at last follow up Alive NED Alive with disease Dead due to disease Dead other cause
Table 6: Univariate Analysis of prognostic factors affecting outcome.
Variable groups
Loco-regional control (p value)
0.77
MBB C
Overall
SBBC
MBBC
Overall
SBBC
MBBC
0.60
0.97
0.47
0.2
0.24
0.2
0.13
0.9
0.71
0.25
0.48
0.085
0.14
0.43
0.23
0.61
0.004
0.002
0.58
0.001
0.001
0.06
0.005
0.03
0.1
0.53
0.56
0.86
0.03
0.01
0.56
0.14
0.13
0.96
0.82
0.55
0.61
0.34
0.86
0.001
0.06
0.6
0.001
0.12
0.2
0.39
0.49
0.49
0.83
0.85
0.9
0.65
0.08
0.10
0.47
0.05
0.09
0.29
0.24
0.31
0.46
0.9
0.7
0.6
0.98
0.96
0.73
0.87
0.96
0.68
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Grade I,II Vs III Histology Ductal Vs Lobular Extensive intraductal component Present Vs Absent Lympho-vascular emboli Present Vs Absent Perineural invasion Present Vs Absent
0.68
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Age (Years) <40 Vs > 40 Menopausal status Premenopausal Vs Postmenopausal Clinical Tumor size <5 cm Vs > 5 cm
SBBC
Overall survival (p value)
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Overall
Disease free Survival (p value)
0.7
0.86
0.82
0.9
0.64
0.71
0.93
0.62
0.009
0.001
0.7
0.07
<0.001
0.05
0.03
<0.001
0.13
NA
0.002
0.51
NA
0.002
0.07
NA
0.002
0.04
0.01
0.007
0.79
0.04
0.002
0.19
0.01
0.002
0.78
0.54
0.91
0.4
0.02
0.04
0.57
0.15
0.04
0.71
0.46
0.07
0.28
0.65
0.42
0.04
0.73
0.7
0.17
0.34
0.44
0.014
0.1
0.01
0.02
0.18
0.008
0.1
0.6
0.002
0.01
0.02
0.005
0.04
0.01
NA
0.32
NA
NA
0.06
NA
NA
0.91
Pathological N stage 0.27 Positive vs Negative PNE Present Vs Absent 0.13 NA
0.27
SC
NA
NA
0.13
NA
NA
0.76
NA
NA
0.06
0.82
<0.001
<0.001
0.02
0.003
0.007
0.10
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0.17
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Interval to second cancer < 3 years vs > 3 years Time of presentation Synchronous Metachronous Surgery MRM vs BCS
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0.9
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Margin status Free (>2mm) Close(<2mm) ER Receptor status Positive Vs Negative ER concordant + Vs Concordant negative Vs Discordant PR Receptor status Positive Vs Negative HER 2 neu + vs. ++ vs. +++ Triple negative Yes vs. No
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S1526-8209(17)30383-X
DOI:
10.1016/j.clbc.2017.11.003
Reference:
CLBC 710
To appear in:
Clinical Breast Cancer
Received Date: 19 June 2017 Revised Date:
3 October 2017
Accepted Date: 2 November 2017
Please cite this article as: Wadasadawala T, Lewis S, Parmar V, Budrukkar A, Gupta S, Nair N, Shet T, Badwe R, Sarin R, Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.11.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population. 1*
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Tabassum Wadasadawala , Shirley Lewis , Vani Parmar , Ashwini Budrukkar , Sudeep Gupta , Nita Nair , Tanuja 5
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Shet , Rajendra Badwe , Rajiv Sarin
1 Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Mumbai
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2 Department of Radiation Oncology, Tata Memorial Centre, Mumbai. 3 Department of Surgical Oncology, Tata Memorial Centre, Mumbai. 4 Department of Medical Oncology, Tata Memorial Centre, Mumbai. 5 Department of Pathology, Tata Memorial Centre, Mumbai.
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Abstract:
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Purpose: Bilateral breast cancer (BBC) is an uncommon presentation. The characteristics and outcomes of synchronous and metachronous BBC were compared within an Indian cohort. Methods: This is a retrospective audit of 193 BBC patients treated at a tertiary hospital in India over a period of 10 years from January 2004 to December 2014.The demographic, tumour and treatment characteristics was compared between synchronous (N=131) and metachronous tumours (62 patients) using descriptive analysis. The survival outcomes were assessed using Kaplan Meier survival curves and compared using log rank test. Univariate and multivariate analysis was done using cox proportional hazards model to assess the impact of the prognostic factors on survival.
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Results: The mean age of presentation in synchronous (SBBC) and metachronous (MBBC) was 55 years (standard deviation (SD): 12.5) and 51 years (SD: 9.5) respectively. The median time to contralateral presentation in MBBC was 3.8 years. Mean tumour size was higher in SBBC (p 0.01). BRCA mutation was positive in 13/38 evaluated patients (of which 12 patients with MBBC). The concordance rates for the estrogen (ER) and progesterone (PR) receptor negativity and triple negative receptor status were higher in MBBC compared to SBBC (p<0.001). Grade III tumour was more frequently seen in MBBC (p=0.03).The median follow up of the entire cohort was 42 months (range 30-60 months): 45 months for SBBC and 35 months for MBBC. The 3 year rates of overall survival (OS), disease free survival (DFS) and locoregional control (LRC) for SBBC and MBBC was 88% and 90%, 74% and 64% and90% and 84%respectively. There was no difference in overall OS, DFS and LRC between SBBC and MBBC.
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Conclusion: Bilateral breast cancer is an uncommon presentation. Synchronous presentation was commoner. Metachronous tumours differ from synchronous with higher grade of presentation and less expression of ER. There was no difference in outcome between synchronous and metachronous tumours. Key words: Bilateral, breast cancer, synchronous, metachronous, survival. Type of manuscript: Original Scientific Article. Running title: Outcomes of Bilateral breast cancer. *Address for Correspondence Dr Tabassum Wadasadawala. Associate Professor, ACTREC, Tata Memorial Centre
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Mumbai - 410210 Email ID: [email protected], [email protected]
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Phone: +91-22-27405079
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Title: Bilateral breast cancer following multimodality treatment- A report of clinical outcome in Asian population.
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Abstract: Purpose: Bilateral breast cancer (BBC) is an uncommon presentation. The characteristics and outcomes of synchronous and metachronous BBC were compared within an Indian cohort. Methods: This is a retrospective audit of 193 BBC patients treated at a tertiary hospital in India from January 2004 to December 2014. The demographic, tumour, treatment characteristics and survival outcomes was compared between synchronous (SBBC)(N=131) and metachronous (MBBC)(62 patients).
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Results: The mean age of presentation in SBBC and MBBC was 55 years ( (SD): 12.5) and 51 years (SD: 9.5) respectively. The median time to contralateral presentation in MBBC was 3.8 years. Mean tumour size was higher in SBBC (p 0.01). BRCA mutation was positive in 13/38 evaluated patients. The concordance rates for the estrogen (ER) and progesterone (PR) receptor negativity and triple negative receptor status were higher in MBBC compared to SBBC (p<0.001). Grade III tumour was more frequently seen in MBBC (p=0.03).The median follow up of the entire cohort was 42 months (range 3060 months). The 3 year rates of overall survival (OS), disease free survival (DFS) and locoregional control (LRC) for SBBC and MBBC was 88% and 90%, 74% and 64% and 90% and 84% respectively. There was no difference in overall OS (p=0.76), DFS (p=0.13) and LRC (p=0.2) between SBBC and MBBC. Conclusion: Synchronous presentation was commoner. Metachronous tumours differ from synchronous with higher grade of presentation and less expression of ER. There was no difference in outcome between synchronous and metachronous tumours.
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Key words: Bilateral, breast cancer, synchronous, metachronous, survival.
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Introduction Breast cancer is the most common cancer among women worldwide and the second most common cause of mortality.[1] Bilaterality is an uncommon presentation and its incidence is about 3-5%.[2,3]The incidence of bilateral breast cancer (BBC) seems to have increased due to improved survival rates after treatment and early detection during follow up with surveillance mammography.[4,5] Various risk factors have been associated with BBC, the most common being lobular histology, hereditary cancers, young age at presentation and positive BRCA mutation.[6,7,8]
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BBC can be classified as synchronous or metachronous based on the time interval of presentation from the first tumour. There is wide variation in literature on the time interval used to define synchronous or metachronous BBC.[9,10,11] Three months is most commonly accepted and described in various large cohort studies.[12] The incidence of synchronous BBC (SBBC) and metachronous BBC (MBBC) described in literature is 0.2-0.3% and 2-20% respectively. [13,14]
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BBC tends to fare poorer than unilateral breast cancers. A recent metaanalysis has shown that SBBC have worse prognosis than unilateral cancers.[15] However, MBBC have a better survival than synchronous.[16] The factors predicting for worse outcomes in MBBC are young age (less than 40 years), short interval to development of contralateral breast cancer (CBC), no adjuvant treatment for the index cancer, symptomatic presentation as compared to screen detected, discordance of receptor status, histology and grade. [11,17,18]
Material and Methods
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There are large institutional series reporting outcome of BBC.[11,12] However, data from Asia and Indian subcontinent is lacking and limited to small numbers.[19] The objective of this study is to present the clinicopathological characteristics, treatment and long term outcome of BBC patients treated at a tertiary care centre in India.
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This is a retrospective audit of BBC patients treated at a tertiary care hospital in India over a period of 10 years from Jan 2004 to December 2014. The data about demographics, tumour characteristics, treatment and outcome was collected from treatment charts, medical records and prospectively maintained databases.
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All patients with an initial diagnosis of invasive breast cancer were included in the study. A 6 month cut off (from the date of initial breast cancer diagnosis) was used to classify synchronous and metachronous bilateral tumors. Oligometastatic patients treated with curative intent were included. All patients received curative multimodality treatment with surgery, chemotherapy and radiation therapy as per institutional protocol. On follow up patients were evaluated biannually with physical examination and with bilateral mammography every 18 months. Males, women with metastatic presentation (at the time of first or second cancer) and patients with missing data or defaulters after diagnosis were excluded. The variables collected were demographics, family history, BRCA mutation status if available, pathological characteristics like tumour size, histology, grade, lymphovascular invasion, axillary nodal status, hormone receptor status and treatment details (surgery, radiotherapy, chemotherapy, hormone therapy and its sequencing). Age refers to the age at the time of diagnosis for first cancer. This is in line with other studies reported earlier.[11,20] Seventh edition of the American Joint Committee on Cancer classification system
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was used for the clinical and pathological staging. The pathology and hormone status was available for all patients. Based on the hormone receptor status of 2 tumours on either side, the SBBC and MBBC were categorised into groups as suggested by Baretta et al: SBBC cohort has 3 groups [concordant positive(+/+), concordant negative (-/-), and discordant (+/- and -/+)] whereas MBBC cohort has 4 groups [concordant positive (+/+), concordant negative (-/-), negative-to positive change (-/+), and positive-tonegative change (+/-)].[21] The vital status was determined through regular follow up examinations by clinicians, telephonic review and house visits.
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For SBBC with similar dates of diagnosis, larger clinical tumour was assigned index cancer for analysis. In the event of similar size, worse grade was taken as index cancer.[12] The survival was measured from the date of diagnosis of index breast cancer in SBBC and second breast cancer in MBBC, in months, until the date of death or date of censoring, 31stDecember 2016, if patients were still alive. For MBBC, survival from first breast cancer was not considered to avoid bias resulting from longer intervals between tumours.
Results
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Statistical Analysis All statistical analysis was done using SPSS version 20. The demographics and tumour characteristics were compared between index synchronous and metachronous tumours using Pearson’s Chi-squared tests for differences in proportions for categorical variables, Mann Whitney U tests for ordinal variables and t-tests for differences in means for continuous variables. Kaplan Meier curves were used to describe overall survival (OS), disease free survival (DFS) and loco-regional control (LRC). OS was defined from date of diagnosis till death or date of censoring. DFS was defined from date of diagnosis to occurrence of relapse (local regional or distant), death or date of censoring. LRC was defined from date of diagnosis till the occurrence of local or regional relapse. Log rank test was used to compare the survival between SBBC and MBBC. Univariate and multivariate analysis was done using cox proportional hazards model to assess the impact of the prognostic factors on survival. All p-values correspond to two-sided tests and values less than 0.05 were considered significant.
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Among 33,941 women diagnosed with invasive breast cancers over the 10-year period, 131 (67%) presented with SBBC and 62 (33%) were diagnosed with MBBC. Synchronous and metachronous accounted for 0.38% and 0.18% of all cases respectively. The median time to contralateral presentation in MBBC was 3.8 years (interquartile range (IQR) 2.8-7). 58% patients had contralateral presentation within 5 years. The demographic and clinical tumour details of index SBBC and MBBC are shown in Table 1. The MBBC were younger than SBBC. The mean age of presentation in SBBC and MBBC was 55 years (standard deviation (SD): 12.5) and 51 years (SD: 9.5) respectively (p=0.05). Overall only 25 patients (13%) were less than 40 year old. Higher positive family history was documented in MBBC compared to SBBC (27% vs. 12%, p=0.009). All patients were advised to consult genetic clinic due to bilaterality especially those with positive family history. However, only 38 patients of the entire cohort were seen in genetic clinic and underwent gene testing. Overall, positive BRCA mutation status was seen in only 13 patients (12 patients were MBBC) of these 38 women tested. Only 6 BRCA positive patients had positive family history. Majority of patients in both groups were postmenopausal (p=0.9). The mean clinical tumour size was larger for SBBC [5.4 cm (SD 3)] compared to MBBC [4.5 cm (SD 2), p=0.01]. In MBBC, mean clinical tumour size of the contralateral breast cancer (CBC) was 3.6 cm (SD 2). Majority of patients were in stage II and III at presentation and infiltrative ductal carcinoma (IDC) was the most common histology in
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both groups. Lobular carcinoma accounted for only 3.6% of SBBC and 1.6-3% of MBBC. Few patients were also treated for oligometastatic bone disease along with the primary with curative intent.
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The hormone receptor status is shown in Table 2. The patients with MBBC had significantly higher rates of ER and PR receptor negativity (p<0.001) as compared to SBBC. ER and PR concordant negative rates were also higher in MBBC. Among SBBC cohort, the two tumors were ER-discordant in 20 (15.3%) patients. In MBBC cohort, the ER negative-to-positive change was observed in 6 (9.5%) patients and the ER positive to-negative change was observed in 8 (13%) patients. Though Her2 status was similar between the 2 groups (about 14-15%), triple negative receptor status was higher in MBBC (p<0.001).
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Majority of patients underwent breast conservation surgery (BCS) in both the groups (p=0.56). Neoadjuvant treatment followed by surgery was the most common approach in over 70% women with SBBC whereas women with MBBC underwent upfront surgery followed by adjuvant chemotherapy and radiation therapy for both index as well as second primary (p=0.001). Three patients received neoadjuvant hormonal therapy in SBBC group. Adriamycin based chemotherapy was most commonly used whereas taxane based chemotherapy was used in about 30%. About 90% of patients received adjuvant radiotherapy. The most common dose used was 50 Gy in 25 fractions to the breast or chest walland tumor bed boost to a dose of 15 Gy in 6 fractions in cases with BCS. The use adjuvant hormone therapy was higher in SBBC owing to higher hormone receptor positivity (p=0.001).
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Table 3 shows the treatment details of the entire cohort. Table 4 shows the pathologic characteristics. Grade III tumour was more frequently seen in MBBC (p=0.03). Ductal carcinoma in situ (DCIS) and extensive intraductal component (EIC) was more frequent in SBBC. Perineural involvement was infrequent. The average number of lymph nodes dissected was 15 with overall low rates of nodal positivity in both the groups.
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The median follow up of entire cohort was 3.5 years (42 months) (IQR 2.5-5 years). The median follow up of SBBC was 4 years (45 months) (IQR 3-6 years) whereas for MBBC it was 3 years (35 months) (IQR 14). The recurrence patterns and disease status is shown in Table 5 (Supplementary material) The median time to event (local, regional or distant) was 2 years for SBBC and 1 year for MBBC. There was no difference in recurrence patterns between SBBC and MBBC (p=0.87) with distant metastases being most common. One patient in SBBC cohort developed second primary in esophagus. There was no difference in OS, DFS and loco-regional control (LRC) between SBBC and MBBC (Figure 1).The median survival (both OS and PFS) was not reached. The 3 year OS for SBBC and MBBC was 88% and 90%, 3 year DFS was 74% and 64% and 3 year LRC was 90% and 84% respectively. The Kaplan Meier estimates for 5 year OS for SBBC and MBBC was 77%, 80%, 5 year DFS was 57% and 51% and 5 year LRC was 84% and 79% respectively. On univariate analysis, the various prognostic factors affecting LRC, DFS and OS are shown in Table 6. (Supplementary material) Univariate analyses of OS for entire cohort indicated significant differences in survival in relation to tumour size (p=0.005), ER receptor status (p=0.03), PR receptor status (p=0.01), node positivity (p=0.02), ECE (p=0.005) and surgery type for index cancer (p=0.003). For SBBC, tumour size >5 cm, ER and PR negative, Her 2 positive, PNE positive and MRM surgery has inferior survival. In SBBC, ER concordant negative tumours had poor survival outcomes compared ER concordant positive and discordant tumours (Figure 2). In MBBC, lobular histology, ER discordant, LN positive and PNE positive had inferior survival but no difference of outcomes when the 4 groups for ER and PR were assessed. On multivariate analysis for entire cohort, clinical tumour size > 5 cm had worse LRC, DFS and OS. Lymphovascular invasion was significant factor affecting LRC. Among the SBBC cohort, clinical
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tumour size > 5 cm was significant for DFS and LRC and PR status for DFS. No factors were significant for OS. Among the MBBC cohort, none of the factors were significant for LRC, DFS and OS. Discussion
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In this study, we report the outcomes of patients with SBBC and MBBC who underwent multimodality treatment at our institute and assessed the prognostic factors affecting outcome. This is the largest study reporting outcomes of bilateral breast cancers from Asia. The results of this study show no difference in OS, DFS and LRC between the SBBC and MBBC groups. Tumour size more than 5 cm was a significant prognostic factor negatively affecting outcome.
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Various factors have been proposed as risk factors for BBC. Some of them are young age, positive family history, multicentricity and lobular histology.[22,23] The mean age of presentation among SBBC was 55 years. The mean age of presentation of index MBBC was 51 years. Though only 13% patients were less than 40 years, the mean age at presentation in our cohort is still lower than that seen in western counterparts. In the study by Nichol et al, the SBBC patients were older with a mean age at presentation of 68 years.[24] Alkner and Baykara et al both reported a median age at diagnosis similar to our cohort.[13,25] In contrast, Yadav et al noted a younger subgroup of patients developing MBBC with over 50% less than 45 years.[26] Hartman et al noted that BBC patients less than 50 years had 3.9 times higher risk of death. [11]
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Beckman compared risk factors between unilateral and BBC and found that BBC was associated with positive family history (p=0.02) and lobular histology (0.04).[12] Yadav et al reported that 15 year risk of CBC in patients with positive family history was 15.3% which is similar to this study.[26] Higher positive family history was noted in MBBC compared to SBBC in our cohort. Baykara et al noted higher positive family history in SBBC (16%).[25] Overall 10% of breast cancer patients carry germ line mutations in BRCA1/2 which predisposes to cancer (annual risk 2-6%).[27] BRCA mutation carriers have a high risk for CBC compared to general population (53% vs 2%).[28] In this study, BRCA positive status was seen in 13 patients of the 38 tested, with higher positivity in metachronous (12 patients) and those with positive family history. Brien et al showed 9 had mutation in 32 tested in BBC cohort.[29] In the present study, lobular carcinoma was seen in only 3% of cases (3% in SBBC and 1.5-3% in MBBC) which is in contrast to the higher incidence reported in western literature to the tune of 16-18%. [12]
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BCS was most commonly used for SBBC (over 50%) as majority underwent down staging with neoadjuvant chemotherapy. There is no consensus on recommended surgical procedure for BBC. Although, it is proposed that the surgical treatment should be on the lines of unilateral breast cancer, practice varies. Mastectomy was commonly employed in SBBC (63%) in study by Nichol et al.[24] Similarly, mastectomy was commonly used for both index and metachronous tumours and BCS employed in only 25-27% in the study reported by Alkner et al.[13] Recent study by Brien et al showed SBBC were less likely to undergo BCS compared to MBBC.[29] The reports in literature comparing outcomes of SBBC and MBBC are conflicting, with few showing equivalent outcomes like the present study [30,31,9] while others showing inferior outcomes for MBBC [11,32,33] or for SBBC.[16,34] There was no difference in survival outcomes between SBBC and MBBC in 150 patients of BBC by Baykara et al with 5 year OS of 90% in both the cohorts.[25] This is consistent with other literature.[29] Beckman et al evaluated the outcomes of BBC in Australian cohort and noted inferior 5 year OS in of 79% in MBBC 79% as compared to 88% in SBBC (p=0.01)[12]
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The median time for CBC development in MBBC was 3.8 years with majority of patients developing second primary within 5 years. Yadav et al studied the risk factors for CBC in Indian population and noted an overall incidence of 4 %. They noted a longer time to development of CBC about 6.3 years.[26] Alkner et al showed that about 42 % developed CBC within 5 years and patients with less than 3 years to CBC had impaired disease free survival particularly in young women.[13] In the present study, about 58% developed a CBC within 5 years and DFI less than 3 years to CBC had poorer disease free survival (p=0.06). Various explanations have been proposed for poor outcome with shorter interval to CBC. CBC could be metastatic spread from index tumour as similarities in terms of morphology and genetics has been noted between tumours. [35,36] These tumours represent an aggressive and resistant phenotype occurring during or shortly after adjuvant treatment.[11]
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ER positivity was low in MBBC. This is consistent with literature.[25,12,37] The treatment of primary breast cancer tends to affect the biology of the second cancer. A change in the hormone receptor status following neoadjuvant treatment or those with relapse has been reported. Discordance of hormone receptors is seen in BBC in about 20% of cases.[38,39] This has been associated with poor survival. Barett et al evaluated the impact of receptor heterogeneity on outcome in BBC. They showed that ER status had more prognostic value over PR status. In SBBC, ER discordant tumours had intermediate OS compared to ER concordant with ER negative tumours faring worst. In MBBC, ER concordant negative and ER positive to negative change patients had poorer survival outcomes.[21] This is also supported by other studies.[40] In the present study, SBBC cohort with ER concordant negative group had inferior LRC, DFS and OS. (Figure 2) Outcomes between ER concordant positive and ER discordant could not be differentiated. In MBBC, OS was inferior among ER negative tumours (p=0.04) but there was no difference in DFS and LRC. There was no difference in outcomes between the four groups for MBBC and effect of positive to negative change could not be appreciated due to very few patient numbers in each group. A hormone receptor change has therapeutic implications for use of chemotherapy and hormone therapy in both SBBC and MBBC thereby affecting outcomes.
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The strengths of this study include large sample size from a single institution from Indian population and reporting of BRCA mutation status though in small proportion of patients. There are a few limitations. The data is abstracted from patients over a span of 10 years with a short median follow up. However, majority of large cohorts have databases of patients over 30-35 years due to the rarity of presentation. Secondly, we could not estimate the mode of detection of second primary (clinically occult or not). Alkner et al showed that in patients with metachronous breast cancer, the patients who presented with symptomatic disease had larger tumours and had a higher chance of distant metastasis compared to those detected by surveillance imaging. In contrast, patients detected to have CBC on mammography were younger and had smaller tumour size.[13] Similarly, Naveen et al showed that even in synchronous BBC, 80% were clinically occult and detected on mammography, had smaller tumour size and better outcome.[19] We have not compared the outcomes of BBC (synchronous or metachronous) with unilateral breast cancer. Various studies have reported the outcomes of BBC in comparison to unilateral tumors.[24,11] Some consider outcome to be similar and few as inferior to unilateral breast cancer. Conclusion
Bilateral breast cancer is an uncommon presentation. Synchronous presentation was commoner compared to metachronous in our cohort. Metachronous tumours differ from synchronous with higher grade of presentation and less expression of ER. There was no difference in OS, DFS and LRC between
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synchronous and metachronous tumours consistent with other cohorts. Tumour size more than 5 cm was the most significant factor negatively affecting outcome and ER negative patients had the worst survival in both synchronous and metachronous cohorts. References
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17. Quan G, Pommier S, Pommier R. Incidence and outcomes of contralateral breast cancers. Am J Surg. 2008;195(5):645–50.
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18. Holmberg L, Adami H, Ekbom A, Bergstrom R, Sandstrom A, Lindgren A. Prognosis in bilateral breast cancer. Effects of time interval between first and second primary tumours. Br Journla cancer. 1988;58(2):191–4. 19. Padmanabhan N, Subramanyan A, Radhakrishna S. Synchronous Bilateral Breast Cancers. J Clin Diagnostic Res. 2015;9(January 2007):3–6. 20. Burns PE, Dabbs K, May C, Lees AW, Birkett LR, Jenkins HJ, et al. Bilateral breast cancer in Northern Alberta: Risk factors and survival patterns. Can Med Assoc J. 1984;130(7):881–6.
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21. Baretta Z, Olopade OI, Huo D. Heterogeneity in hormone-receptor status and survival outcomes among women with synchronous and metachronous bilateral breast cancers. Breast . Elsevier Ltd; 2015;24(2):131–6. 22. Li CI, Malone KE, Porter PL, Daling JR. Epidemiologic and molecular risk factors for contralateral breast cancer among young women. Br J Cancer. 2003;89(3):513–8.
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23. Malone KE, Daling JR, Weiss NS, McKnight B, White E, Voigt LF. Family history and survival of young women with invasive breast carcinoma. Cancer. 1996;78(7):1417–25.
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24. Nichol AM, Yerushalmi R, Tyldesley S, Lesperance M, Bajdik CD, Speers C, et al. A case-match study comparing unilateral with synchronous bilateral breast cancer outcomes. J Clin Oncol. 2011;29(36):4763–8. 25. Baykara M, Ozturk SC, Buyukberber S, Ozdemir N, Alkis N, Berk V, et al. Clinicopathological Features in Bilateral Breast Cancer. 2012;13:4571–5. 26. Yadav BS, Sharma SC, Patel FD, Ghoshal S, Kapoor RK. Second primary in the contralateral breast after treatment of breast cancer. Radiother Oncol. 2008;86(2):171–6. 27. NN B, S I, J H, S L, M B. Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis. Fam Cancer. 2015;14(4):531–8. 28. Nicoletto MO, Donach M, Nicolo A De, Artioli G, Banna G, Monfardini S. BRCA-1 and BRCA-2
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mutations as prognostic factors in clinical practice and genetic counselling. 2001; 29. A OJ, Alice H, Paul W, Michelle S, Sujata P, Kate K, et al. Breast-Conserving Surgery in Bilateral Breast Cancer. Ann Surg Oncol. 2015;22(10):3389–96.
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33. 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(4):388–91. 34. Ibrahim NY, Sroor MY, Darwish DO. Impact of bilateral breast cancer on prognosis: Synchronous versus metachronous tumors. Asian Pacific J Cancer Prev. 2015;16(3):1007–10.
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35. Imyanitov EN, Suspitsin EN, Grigoriev MY, Togo A V., Kuligina ES, Belogubova E V., et al. Concordance of allelic imbalance profiles in synchronous and metachronous bilateral breast carcinomas. Int J Cancer. 2002;100(5):557–64. 36. Hemminki K, Granström C. Morphological types of breast cancer in family members and multiple primary tumours: is morphology genetically determined? Breast Cancer Res [Internet]. 2002;4(4):R7.
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Table 1: Baseline patient demographic and clinical tumour details. Metachronous P value Second NA 0.059
NA NA
23 (37%) 5 (8%) 34 (55%) 4.5 (SD 2)
44 (33.6%) 40 (30.5%) 2 (1.5%) 72 (55%) 50 (38%) 4 (3%) 3 (2.5%)
33 (53%) 12 (19.5%) 1 (1.5%) 36 (58%) 25 (40.5%) -
37 (60%) 9 (14.5%) 11 (18%) 30 (48.5%) 20 (32%) 1 (1.5%)
124 (94.8%) 5 (3.6%) 2 (1.6%)
61 (98.5%) 1 (1.5%) -
59 (95.5%) 2 (3%) 1 (1.5%)
0.009 0.28
SC
34 (26%) 13 (10%) 84 (64%) 4.5 cm (SD 2)
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Metachronous (n=62) Index 27 (43.5%) 35 (56.5%) 17 (27.4%)
3.6 (SD 2)
0.01 0.1
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Age (years) : ≤ 50 50 -69 ≥ 70 Positive family history Menopausal status: Pre Peri Post Mean tumour size Involved quadrant: Upper outer Central Clinical stage: I II III IV NK Histology: Infiltrative ductal Infiltrative lobular Ductal carcinoma in situ
Synchronous (n=131) 46 (35%) 70 (53.5%) 15 (11.5%) 16 (12.2%)
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Characteristics
0.2
0.9
Characteristics
Synchronous (n=131) Index Second 84 (64%) 88 (67%) 47 (36%) 43 (33%)
Metachronous (n=62) Index Second 21 (34%) 20 (32%) 41 (66%) 42 (68%)
76 (58%) 35 (36.7%) 20 (15.3%)
13 (21%) 35 (56.5%) 8 (13%) 6 (9.5%) 17 (27.5%) 45 (72.5%)
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ER: Positive Negative ER: Concordant positive Concordant negative Discordant +/-/+ PR: Positive Negative PR: Concordant positive Concordant negative Discordant +/-
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Table 2: Hormone receptor status.
72 (55%) 58 (44%)
P value <0.001 <0.001
80 (61%) 51 (39%)
19 (30.5%) 43 (69.5%)
<0.001 <0.001
64 (48.9%) 42 (32.1%) 25 (19.1%)
9 (14.5%) 37 (59.7%) 7 (11.3%)
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20 (15.2%) 15 (11.5%) 96 (73.3%) 103 (78.5%) 15 (11.5%) 13 (10%)
9 (14.5%) 7 (11%) 51 (82%) 4 (6%)
Triple Negative
16 (12.2%)
26 (42%)
9 (14.5%) 49 (79%) 4 (6.5%)
<0.001
Table 3: Treatment details
Metachronous (n=62) Index Second
P value
69 (52.5%) 62 (47.5%) 0
28 (45%) 34 (55%) 0
0.56
42 (32.5%) 3 (2%) 76 (58%) 86 (65.6%)
SC
39 (63%) 11(17.7%)
29 (46.7%) 9 (14.5%)
12 (19.3%)
16 (25.8%)
-
-
23 (37%) 50 (80%)
21 (34%) 29 (46%)
NA
0.001
0.23
117 (89%) 10 (8%) 4 (3%)
58 (93.5) 3 (5) 1 (1.5)
96 (73) 35(27)
27 (43.5) 35 (56.5)
33 (34) 63 (66)
12 (44.5) 15 (55.5)
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38 (61%) 22 (36%) 2 (3%)
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52 (39.5%) 34 (26%)
66 (50.5%) 64 (48.5%) 1 (1%)
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Surgery: BCS MRM/SMAC Done but type not known Treatment Sx CT RT ± HT NACT Sx CT RT ± HT NACT/NHT Sx RT ± HT NAHT Sx RT ± HT Chemotherapy : Neoadjuvant Adjuvant Radiotherapy Yes No NK Hormone therapy Yes No HT agent Tamoxifen AI
Synchronous (n=131) Index Second
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Characteristics
0.78
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-/+ Her 2: Positive Negative Equivocal
0.001
NA
Table 4: Pathologic characteristics. Characteristics Stage 0 I II III Grade I/II
Synchronous (n=131) Index Second 13 (10%) 16 (12%) 28 (21%) 21 (16%) 38(44%) 58 (44.5%) 52 (25%) 36 (27.5%) 40 (30.5%) 42 (32%)
Metachronous (n=62) Index Second 7 (11.5%) 12 (19.5%) 12 (19%) 14 (22.5%) 26 (42%) 26 (42%) 17 (27.5%) 10 (16%) 14 (22.5%) 11 (18%)
P value 0.24
0.03
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89 (68%) 62 (47%) 29 (22%) 3 (3.3%) 12 (9%) 0.7 cm
48 (77.5%) 17 (27.5%) 8 (13%) 3 (5%) 4 (6.5%) 0.7 cm
51 (82%) 16 (26%) 10 (16%) 0 1 (1.5%) 0.8 cm
15 2 43 (33%)
15 8 55 (42%)
15 2 8 (29.6%)
16 2 13 (21%)
Table 5: Recurrence patterns and disease status.
0.09 0.07
Metachronous (n= 62) 22 (35.5%) 4 (18.2%) 4 (18.2%) 14 (63.6%) -
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Synchronous (n= 131) 45 (34.4%) 8 (17%) 6 (13.5%) 30 (67%) 1 (2.2%) 81 (62%) 20 (15%) 22 (17%) 8 (6%)
41 (66%) 11 (16%) 10 (18%) -
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Recurrence rate: Loco-regional Loco-regional + Distant Distant Second primary Status at last follow up Alive NED Alive with disease Dead due to disease Dead other cause
0.005 0.34 0.29 0.02 0.5
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91 (69.5%) 70 (53.4%) 32 (24.5%) 10 (8%) 15 (11.5%) 0.8 cm
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III DCIS + LVI + PNI + EIC + Margins (Mean) Axillary Lymph nodes (Mean) Dissected Positive Perinodal extension(PNE)
Loco-regional control (p value)
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Variable groups
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Table 6: Univariate Analysis of prognostic factors affecting outcome.
Age (Years) <40 Vs > 40 Menopausal status Premenopausal Vs Postmenopausal Clinical Tumor size <5 cm Vs > 5 cm Grade I,II Vs III
Disease free Survival (p value)
Overall survival (p value)
Overall
SBBC
MBB C
Overall
SBBC
MBBC
Overall
SBBC
MBBC
0.68
0.60
0.97
0.47
0.2
0.24
0.2
0.13
0.9
0.77
0.71
0.25
0.48
0.085
0.14
0.43
0.23
0.61
0.004
0.002
0.58
0.001
0.001
0.06
0.005
0.03
0.1
0.53
0.56
0.86
0.03
0.01
0.56
0.14
0.13
0.96
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0.55
0.61
0.34
0.86
0.001
0.06
0.6
0.001
0.12
0.2
0.39
0.49
0.49
0.83
0.85
0.9
0.65
0.08
0.10
0.47
0.05
0.09
0.29
0.24
0.31
0.46
0.9
0.7
0.6
0.98
0.96
0.73
0.87
0.96
0.68
0.9
0.7
0.86
0.82
0.9
0.64
0.71
0.93
0.62
0.009
0.001
0.7
0.07
<0.001
0.03
<0.001
0.13
NA
0.002
0.51
NA
0.002
0.07
NA
0.002
0.04
0.01
0.007
0.79
0.04
0.002
0.19
0.01
0.002
0.78
0.54
0.91
0.4
0.02
0.04
0.57
0.15
0.04
0.71
0.46
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0.05
0.07
0.28
0.65
0.42
0.04
0.73
0.7
0.17
0.34
0.44
0.014
0.1
0.01
0.02
0.18
0.008
0.1
0.6
0.002
0.01
0.02
0.005
0.04
0.01
NA
NA
0.32
NA
NA
0.06
NA
NA
0.91
0.27
NA
NA
0.13
NA
NA
0.76
NA
NA
0.17
0.06
0.82
<0.001
<0.001
0.02
0.003
0.007
0.10
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Pathological N stage 0.27 Positive vs Negative PNE Present Vs Absent 0.13 Interval to second cancer < 3 years vs > 3 years Time of presentation Synchronous Metachronous Surgery MRM vs BCS
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0.82
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Histology Ductal Vs Lobular Extensive intraductal component Present Vs Absent Lympho-vascular emboli Present Vs Absent Perineural invasion Present Vs Absent Margin status Free (>2mm) Close(<2mm) ER Receptor status Positive Vs Negative ER concordant + Vs Concordant negative Vs Discordant PR Receptor status Positive Vs Negative HER 2 neu + vs. ++ vs. +++ Triple negative Yes vs. No
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Figures
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Figure 1: Kaplan Meier graph for overall survival(A), disease free survival (B) and locoregional control (C) comparing synchronous with metachronous.
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Figure 2: Kaplan Meier graph for overall survival(A), disease free survival (B) and locoregional control (C) comparing ER concordant and discordant tumours in SBBC.
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Supplementary material Table 5: Recurrence patterns and disease status. Metachronous (n= 62) 22 (35.5%) 4 (18.2%) 4 (18.2%) 14 (63.6%) -
81 (62%) 20 (15%) 22 (17%) 8 (6%)
41 (66%) 11 (16%) 10 (18%) -
SC
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Synchronous (n= 131) 45 (34.4%) 8 (17%) 6 (13.5%) 30 (67%) 1 (2.2%)
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Recurrence rate: Loco-regional Loco-regional + Distant Distant Second primary Status at last follow up Alive NED Alive with disease Dead due to disease Dead other cause
Table 6: Univariate Analysis of prognostic factors affecting outcome.
Variable groups
Loco-regional control (p value)
0.77
MBB C
Overall
SBBC
MBBC
Overall
SBBC
MBBC
0.60
0.97
0.47
0.2
0.24
0.2
0.13
0.9
0.71
0.25
0.48
0.085
0.14
0.43
0.23
0.61
0.004
0.002
0.58
0.001
0.001
0.06
0.005
0.03
0.1
0.53
0.56
0.86
0.03
0.01
0.56
0.14
0.13
0.96
0.82
0.55
0.61
0.34
0.86
0.001
0.06
0.6
0.001
0.12
0.2
0.39
0.49
0.49
0.83
0.85
0.9
0.65
0.08
0.10
0.47
0.05
0.09
0.29
0.24
0.31
0.46
0.9
0.7
0.6
0.98
0.96
0.73
0.87
0.96
0.68
AC C
Grade I,II Vs III Histology Ductal Vs Lobular Extensive intraductal component Present Vs Absent Lympho-vascular emboli Present Vs Absent Perineural invasion Present Vs Absent
0.68
EP
Age (Years) <40 Vs > 40 Menopausal status Premenopausal Vs Postmenopausal Clinical Tumor size <5 cm Vs > 5 cm
SBBC
Overall survival (p value)
TE D
Overall
Disease free Survival (p value)
0.7
0.86
0.82
0.9
0.64
0.71
0.93
0.62
0.009
0.001
0.7
0.07
<0.001
0.05
0.03
<0.001
0.13
NA
0.002
0.51
NA
0.002
0.07
NA
0.002
0.04
0.01
0.007
0.79
0.04
0.002
0.19
0.01
0.002
0.78
0.54
0.91
0.4
0.02
0.04
0.57
0.15
0.04
0.71
0.46
0.07
0.28
0.65
0.42
0.04
0.73
0.7
0.17
0.34
0.44
0.014
0.1
0.01
0.02
0.18
0.008
0.1
0.6
0.002
0.01
0.02
0.005
0.04
0.01
NA
0.32
NA
NA
0.06
NA
NA
0.91
Pathological N stage 0.27 Positive vs Negative PNE Present Vs Absent 0.13 NA
0.27
SC
NA
NA
0.13
NA
NA
0.76
NA
NA
0.06
0.82
<0.001
<0.001
0.02
0.003
0.007
0.10
EP
0.17
AC C
Interval to second cancer < 3 years vs > 3 years Time of presentation Synchronous Metachronous Surgery MRM vs BCS
RI PT
0.9
M AN U
Margin status Free (>2mm) Close(<2mm) ER Receptor status Positive Vs Negative ER concordant + Vs Concordant negative Vs Discordant PR Receptor status Positive Vs Negative HER 2 neu + vs. ++ vs. +++ Triple negative Yes vs. No
TE D
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