Multiple Breast Carcinomas Research Articles

Bilateral oncoplastic breast-conserving surgery with volume replacement technique using the omental flap: a case report

BackgroundMany oncoplastic volume replacement techniques have been reported, however, it is generally difficult to utilize a single distant flap for bilateral breast carcinomas.Case presentationWe report a case of bilateral multiple breast carcinomas successfully treated with immediate volume replacement technique with an omental flap. Bilateral partial mastectomies were performed for bilateral breast carcinomas (one in the left breast and two in the right breast). The pedicled omental flap was laparoscopically harvested, and divided at the mid-portion of the flap. The proximal half of the flap was used to fill the right defect, and the distal half of the flap filled two defects in the left breast. Cosmetic outcome was excellent with minimal donor-site scars.ConclusionsThe omental flap can be considered for highly selected patients with bilateral breast carcinomas.

ASO Author Reflections: Age Is an Important Determinant of Concordance Between 21-Gene Recurrence Scores in Multiple Ipsilateral Breast Carcinomas

ASO Author Reflections: Age Is an Important Determinant of Concordance Between 21-Gene Recurrence Scores in Multiple Ipsilateral Breast Carcinomas

Abstract P3-07-09: Tumour clonality in paired invasive breast carcinomas

Abstract Background: Multiple invasive breast tumours may represent either independent primary tumours or clonal recurrences of the first tumour, where the same progenitor cell gives rise to all of the detected tumours. Consequently, the driver events for the progenitor cell need to have been identical in early tumour development. Molecular classification of tumour clonality is not currently evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. Furthermore, there is no consensus about which type of biological data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours. Methods: Thirty-seven invasive breast tumour pairs were stratified by laterality (bilateral vs. ipsilateral) and the time interval between the diagnoses of the first and second tumours (synchronous vs. metachronous). Both tumours from the same patient were analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), distance measure, shared segment analysis etc., were used to classify the tumours from the same patient as clonally related recurrences or independent primary tumours. Results: The SI applied on DNA copy numbers derived from aCGH (array comparative genomic hybridization) data was determined as the strongest indicator of clonal relatedness as it showed the highest concordance with all other methods. The distance measure was the most conservative method and the shared segment analysis most liberal. Concordant evidence for tumour clonality was found in 46% (17/37) of the patients. Notably, no significant association was found between the clinical characteristics and molecular tumour features. Conclusions: A more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. In cases of extremely similar or different tumour pairs, the results showed consistency regardless of the method used. The SI can be easily integrated into clinical routine using FFPE samples to obtain copy number data. However, clinical guidelines with exact thresholds need to be defined to standardize clonality testing in a routine diagnostic setting. Citation Format: Biermann J, Parris TZ, Nemes S, Danielsson A, Engqvist H, Werner Rönnerman E, Forssell-Aronsson E, Kovács A, Karlsson P, Helou K. Tumour clonality in paired invasive breast carcinomas [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-09.

Multifocal/Multicentric Ipsilateral Invasive Breast Carcinomas with Similar Histology: Is Multigene Testing of All Individual Foci Necessary?

Multiple synchronous ipsilateral invasive breast carcinomas (BCs) with similar histology usually have concordant receptor status. It is unknown whether individual foci with similar histology also share molecular and biological similarities or are heterogenous. This study examined the concordance of the 21-gene recurrence score (RS) in multiple synchronous morphologically similar ipsilateral BCs. We identified patients with multiple ipsilateral BCs and available RS treated at our institution from 1/2014 to 6/2018. BCs were divided into three groups based on RS: (1) RS in same risk category, (2) RS in different risk categories but within 2-unit difference (e.g., RS 17 and RS 19), and (3) RS in different risk categories and a change of > 2 units. BCs in groups 1 and 2 were considered as concordant (no significant clinical impact) and BCs in group 3 as discordant (variation affects management). A total of 53 patients met the study criteria. RS was concordant in 46 (87%) cases. Seven (13%) cases were discordant (group 3). Of these, three (43%, 3/7) had biopsy cavity changes (BXC) adjacent to the BC with highest RS. In two cases the focus with higher RS had a lower percentage of progesterone receptor-positive tumor cells. In two cases, extensive ductal carcinoma in situ was associated with the BC focus with lower RS. Morphologically similar multifocal ipsilateral BCs have concordant RS in 87% (46/53) of cases. Our results suggest that, in cases of morphologically similar multifocal BCs, testing of a single focus provides accurate prognostic and predictive information.

Evaluation of Biomarkers in Multiple Ipsilateral Synchronous Invasive Breast Carcinomas.

The College of American Pathologists guidelines recommend testing additional tumor foci in multifocal invasive breast carcinomas for the biomarkers estrogen receptor (ER), progesterone receptor, and HER2 only if the carcinomas show different morphologies or grades. To assess clinical significance of testing for biomarkers in additional tumor foci in multifocal invasive breast tumors. Retrospective analysis of 118 patients diagnosed with ipsilateral synchronous multifocal breast carcinomas from January 2015 through March 2016 at Mount Sinai Hospital (New York, New York). Eighty-six cases were tested for at least 1 of the 3 biomarkers in additional tumor foci. Fifteen cases (17%) showed discordant staining between the 2 foci for at least one biomarker. Of the 7 of 67 ER-discordant cases (10%), 4 (57%) showed major variation from negative to positive expression, including 3 cases in which a smaller tumor focus was strongly positive for ER whereas the index tumor was negative. Similarly, within the 7 of 67 progesterone receptor-discordant cases (10%), 4 (57%) showed major variation from negative to positive, and in 3 cases with major discordance, the index tumor was negative for progesterone receptor, whereas a smaller focus was positive. A difference in HER2 expression was noted in 5 of 86 cases (6%). In only 5 of the 15 patients (33%) with discordant results, biomarker testing on additional foci would have been offered per the College of American Pathologists recommendations because of differences in histology or grading. Of the remaining 10 patients, 7 (70%) with positive results on smaller foci would have been deprived of appropriate adjuvant systemic treatment if the smaller focus had not been tested. We propose that negative values expressed in the primary tumor be repeated routinely on additional ipsilateral synchronous tumors.

Clonal relatedness in tumour pairs of breast cancer patients

BackgroundMolecular classification of tumour clonality is currently not evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. There is no consensus about which type of data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours.MethodsThirty-seven invasive breast tumour pairs were stratified according to laterality and time interval between the diagnoses of the two tumours. In a multi-omics approach, tumour clonality was analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), were used to classify the tumours as clonally related recurrences or independent primary tumours.ResultsThe SI and hierarchical clustering showed similar tendencies and the highest concordance with the other methods. Concordant evidence for tumour clonality was found in 46% (17/37) of patients. Notably, no association was found between the current clinical guidelines and molecular tumour features.ConclusionsA more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. Guidelines need to be defined with exact thresholds to standardise clonality testing in a routine diagnostic setting.

Colonic metastasis from breast carcinoma: a case report

BackgroundColonic metastasis from breast carcinoma is very rare. Here, we report a case of colonic metastasis from breast carcinoma.Case presentationThe patient was a 51-year-old woman. She had upper abdominal pain, vomiting, and diarrhea, repeatedly. We performed abdominal contrast-enhanced computed tomography (CT) to investigate these symptoms. The CT scan revealed a tumor in the ascending colon with contrast enhancement and showed an expanded small intestine. For further investigation of this tumor, we performed whole positron emission tomography-computed tomography (PET-CT). The PET-CT scan revealed fluorodeoxyglucose uptake in the ascending colon, mesentery, left breast, and left axillary region. Analysis of biopsy samples obtained during colonoscopy revealed signet ring cell-like carcinoma. Moreover, biopsy of the breast tumor revealed invasive lobular carcinoma. Therefore, the preoperative diagnosis was colonic metastasis from breast carcinoma. Open ileocecal resection was performed. The final diagnosis was multiple metastatic breast carcinomas, and the TNM classification was T2N1M1 Stage IV.ConclusionsWe presented a rare case of colonic metastasis from breast carcinoma. PET-CT may be useful in the diagnosis of metastatic breast cancer. When analysis of biopsy samples obtained during colonoscopy reveals signet ring cell-like carcinoma, the possibility of breast cancer as the primary tumor should be considered.

Discordance Rate in Estrogen Receptor, Progesterone Receptor, HER2 Status, and Ki67 Index Between Primary Unifocal and Multiple Homogenous Breast Carcinomas and Synchronous Axillary Lymph Node Metastases Have an Impact on Therapeutic Decision.

Background:We aimed to demonstrate that in breast carcinomas the tumor profile is not stable during the metastatic process, with impact on therapeutic decisions.Materials and Methods:We analyzed the estrogen receptor (ER), progesterone receptor (PR), and HER2 status and Ki67 index in 41 primary unifocal (PU) and 37 primary multiple (PM) breast carcinomas with identical immunohistochemical profiles among multiple tumor foci and the matched axillary lymph node metastases. We defined as concordant cases in which the primary tumor (PU or PM) and lymph node metastases displayed identical positivity or negativity for ER, PR, HER2, Ki67 and as discordant cases in which there was a mismatch in at least 1 biological parameter among PU and PM tumor and lymph node metastases. Moreover, we defined as concordant cases in which the molecular profile (based on the immunohistochemical evaluation of ER, PR, HER2, and Ki67) was concordant among PU and PM tumors and lymph node metastases and mismatch cases as those in which the molecular profile of the primary tumor differs from one of the lymph node metastases in at least 1 lymph node.Results:The positivity for the biological markers is not stable during the metastatic process. In this study the total rate of discordant cases was 92.7% in PU tumors and 75.7% in PM homogenous tumors (P=0.058, odds ratio=0.245, 95% confidence interval, 0.06-0.991). The total rate of shifted cases was 64.9% in PM tumors and 82.9% in PU tumors. The highest rate of shifting was encountered from Luminal B-like to Luminal A-like. In 11 out of 37 (29.7%) PM and in 17 out of 41 (41.5%) PU cases the subtype shifted to a poorer one with respect to prognosis.Conclusions:The patients in whom the primary tumor is hormone receptor and/or HER2 negative but is positive for these markers in the axillary lymph nodes could become eligible for hormonal treatment and/or trastuzumab treatment, which may significantly improve the patient’s outcome.

Review on Practical Approach in Multiple Breast Carcinomas: Does Each Focus Matter?

Breast carcinoma is the most frequent form of cancer encountered in women worldwide. In the routine practice, most of breast carcinomas are diagnosed as unifocal, however, a variable proportion is represented by multiple tumor foci. Since data regarding the incidence, definition, morphological and molecular profile, treatment and prognosis of multiple breast carcinomas are currently contradictory we are presenting a practical approach for pathologists dealing with such a lesion, which may display morphological and molecular heterogeneity among multiple foci with an impact on management and prognosis. Multiple tumor foci should be reported separately and taken into account when establishing the treatment.

Multiple breast carcinomas showing intratumoral heterogeneity: a comparison between histological features of the primary tumor and lymph node metastasis

Background Our study aims to analyze the histological profile of lymph node metastases in multiple breast tumors in which primary tumor foci have different histological features. Methods We reassessed slides from consecutive multiple breast carcinomas surgically treated between 2007 and 2012, with complete axillary lymph node dissection. We selected cases with multiple foci displaying different histology and compared them with cases displaying similar histology. Results 155 (19.23%) of 806 cases had multiple breast cancer, of which 23 cases (14.83%) had foci with different morphology and 132 cases had similar morphology. Of the latter, 99 cases had axillary lymph node metastases morphologically identical to the originating breast tumors. Nineteen of the 23 cases with dissimilar morphology (82.6%) had axillary lymph node metastases. In most of these cases (17/19) (89.47%), the metastases had the same histological features as the tumor with the highest histological grade (G3). In 5/19 cases (26.31%), metastases had the features of one of the smaller tumor foci. Conclusions The histology of axillary lymph node metastases in multiple breast carcinomas corresponds to the highest histological grade and/or most aggressive histological type of the primary tumor, which is not necessarily the largest one.

Morphologic and molecular subtype status of individual tumor foci in multiple breast carcinoma. A study of 155 cases with analysis of 463 tumor foci

The aim of this study is to evaluate biomarker immunophenotypic heterogeneity between separate tumor foci of multiple breast carcinoma, its correlation with morphologic features and tumor grade, and its influence on the treatment. One hundred fifty-five invasive multiple breast carcinomas were retrospectively analyzed over a 6-year period (2007-2012), and the expression of estrogen (ER) and progesterone (PR) receptors, Ki-67 proliferative index, human epidermal growth factor receptor 2 expression, morphologic subtype, and tumor grading were analyzed in each tumor focus. We found mismatches in immunohistochemical features in 71 (53.78%) of 132 patients with similar histology and in 13 (56.52%) of 23 cases with different histology. When analyzing mismatches in ER and PR statuses together, in 4 (23.52%) of 17 cases, one of the tumor foci was ER or PR positive, whereas the index tumor did not express either marker. The most numerous mismatches (45 cases; 29.03%) concerned the proliferative index; in 14 cases (9.03%), the additional focus had a higher index than did the main focus, and in 9 of these cases, the additional focus displayed a histologic grade of 3. Mismatches in human epidermal growth factor receptor 2 status appeared in 25 (16.12%) cases. The histologic type of the additional foci was different from the index tumor in 23 (14.83%) cases. Assessment of all tumor foci would have determined 19 (12.25%) cases to receive different adjuvant treatments compared with what would have been indicated if only the biological status of the largest primary tumor was assessed. We strongly recommend assessing and reporting each tumor focus independently.

Abstract P6-07-28: Assessment of T stage in the multiple breast carcinomas

Abstract Background: Tumor size is an important predictor of nodal metastasis, recurrence, distant metastasis in invasive breast carcinomas. T stage assignment of the multiple simultaneous ipsilateral breast carcinomas is based on the largest tumor with the suffix “(m)” to indicate multiplicity in the AJCC staging, and sum of the sizes should not be used. The aim of this study is to compare current AJCC staging and two test models using the aggregate of all tumor foci and the aggregate of all tumor volume in the single and multiple breast carcinomas. Methods: We reviewed original pathologic reports of 1145 consecutive patients with invasive ductal carcinoma, 2003–2004. 131 (11.4%) patients had multiple masses. Three factors were used to compare T stages; (1) the greatest dimension of the largest invasive component (T), (2) the aggregate of all tumor foci (TA), and (3) the aggregate of all tumor volume (TV). T stage follows AJCC (7th ed, 2010) system. TA and TV were categorized as followings: TA1 < 2cm, 2cm ≤ TA2 < 5cm and TA3 ≥ 5cm; TV1 < 8cm³ (average diameter < 2cm), 8 cm³ ≤ TV2 < 125cm³ and TV3 ≥ 125cm³ (average diameter ≥ 5cm). Clinicopathologic parameters were analyzed according to T stage. Results: Axillary lymph node metastasis was more common in the cases with multiple masses (64/131, 48.9%) than single mass (397/1014, 39.2%) and the number of the metastatic lymph node was also higher in multiple cases. Multiple breast carcinomas tended to show frequent recurrence, and disease specific death compared with the single cases in the same stage. (p < 0.05) Among 606 cases of T1, 34 cases were reclassified to TA2 and in 487 cases of the T2, 23 cases were reclassified to TA3. TV also showed reclassification of the cases. Multiplicity, T stage, TA stage, and TV stage were significant factors for nodal positivity in the univariate analysis (p < 0.05). Nodal positivity was remained in the multivariate analysis for recurrence and disease specific death, but the other factors were not significant for nodal involvement, recurrence and disease specific death. Conclusion: Multiple breast carcinomas has adverse patients' outcome than single carcinoma with same T stage of AJCC system and a better staging method is required to cover multiple carcinomas. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-28.

Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm(3)) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns.

Discrimination between multicentric and multifocal breast carcinoma by cytogenetic investigation of macroscopically distinct ipsilateral lesions.

Whether macroscopically distinct carcinomas in the same breast are clonally related (multifocal breast carcinoma) or unrelated (multicentric breast carcinoma) is no longer only a scientific-pathological issue but, because different therapeutic strategies may be preferable for cases with intramammary metastatic disease compared with cases of multiple primary breast carcinomas, one that may have profound clinical implications. We studied the evolutionary relationship among macroscopically distinct, ipsilateral breast carcinomas by cytogenetic analysis of 26 tumorous lesions from 12 patients. Sixteen of the 26 foci (62%) were found to contain clonal chromosome abnormalities. Two carcinoma foci were karyotypically abnormal in each of seven patients. Four of these cases had an evolutionarily related, cytogenetically abnormal clone in the two lesions from the same breast, whereas the remaining three cases had completely different clonal karyotypic aberrations in the separate foci. These results, together with our previous findings in five other informative cases, show that multiple, synchronous breast tumors sometimes arise through intramammary spreading of a single primary carcinoma, whereas on other occasions they are the result of the simultaneous emergence of pathogenetically independent carcinomas within the breast. In the total material, an association was seen between the proximity of the foci and the likelihood of them being karyotypically related.

Discrimination between multicentric and multifocal carcinomas of the breast through clonal analysis

An unanswered, important question concerning multiple breast carcinomas is whether they arise independently in the breast (multicentric) or are metastatic deposits from a single, primary carcinoma (multifocal). This issue was studied by clonal analysis of each focus of multiple breast carcinomas. First, the clonality of 30 breast carcinomas was analyzed by the method based on restriction fragment length polymorphism of the X-chromosome-linked phosphoglycerokinase (PGK) gene and on random inactivation of the gene. Second, the clonality of each focus of three multiple breast carcinomas was analyzed by the same method. Clonal analysis of the 30 breast carcinomas revealed that every carcinoma was monoclonal in origin, and one of two alleles of the PGK gene was inactivated at random in these carcinomas. Three patients with multiple breast carcinomas had three, three, and four histologically separate foci of carcinoma in the breast, respectively. Clonal analysis showed that each focus was monoclonal in origin and, in addition, the same allele of the PGK gene was inactivated consistently at each focus in every patient. The thesis that multiple carcinoma foci arise independently is unlikely to be true, because the probability that every independent focus happens to inactivate the same allele of PGK gene in every patient is very low. It seems more likely that a single primary carcinoma spreads throughout the breast to culminate in multiple secondary carcinoma foci. Therefore, it is concluded that multiple breast carcinomas are multifocal and not multicentric in origin.