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Association between the histopathological growth patterns of liver metastases and survival after hepatic surgery in breast cancer patients

Association between the histopathological growth patterns of liver metastases and survival after... www.nature.com/npjbcancer BRIEF COMMUNICATION OPEN Association between the histopathological growth patterns of liver metastases and survival after hepatic surgery in breast cancer patients 1,13 2,3,13 4 2 3 4 4 Ali Bohlok , Peter Vermeulen , Sophia Leduc , Emily Latacz , Lara Botzenhart , François Richard , Maxim De Schepper , 4 5 6 7 8 6 9 Tatjana Geukens , Valerio Lucidi , Michail Ignatiadis , Philippe Aftimos , Christos Sotiriou , Martine Piccart , Alain Hendlisz , 2 2,3 10 11 12 4,13 Steven Van Laere , Luc Dirix , Jean-Christophe Noël , Elia Biganzoli , Denis Larsimont , Christine Desmedt and 1,13 Vincent Donckier Currently, there are no markers to identify patients with liver-only or liver-dominant metastases that would benefit from hepatic surgery. Here we characterized histopathological growth patterns (HGPs) of liver metastases in a consecutive series of 36 breast cancer patients who underwent hepatic surgery. Survival analyses showed that the presence of a desmoplastic HGP in the liver metastases (a rim of fibrous tissue separating cancer cells from the liver parenchyma, present in 20 (56%) patients) is independently associated with favorable progression-free and overall survival when compared with the replacement HGP (cancer cells growing into the liver parenchyma, present in 16 (44%) patients). npj Breast Cancer (2020) 6:64 ; https://doi.org/10.1038/s41523-020-00209-1 Even if metastatic breast cancer is frequently considered as a desmoplastic pattern (D-HGP), cancer cells are separated from liver systemic disease, local treatment targeting metastases may result cells by a rim of desmoplastic stroma, which is often densely 1–4 in prolonged survival in selected cases . In particular, in patients infiltrated with inflammatory cells. In the D-HGP, tumor vasculariza- with liver-only or liver-dominant metastases, surgical resection of tion is provided by angiogenesis. In colorectal patients undergoing liver metastases (LM) is associated with survival between 22 and resection of LM, the R-HGP is associated with worse postoperative 7–9 61 months and long-term progression-free survival (PFS) in survival as compared to D-HGP LM . Here we aimed at scoring selected cases , serving as a proof of concept for an oligometa- and evaluating the prognostic value of HGP in patients with breast static status in a subgroup of patients. At present, however, there cancer undergoing resection of LM. Consecutive patients with breast cancer who underwent surgical are no established biomarkers to identify this subgroup . resection for LM at the Institut Jules Bordet and the Hôpital Erasme Furthermore, no factor has been reliably associated with rapid (Brussels, Belgium) between April 2000 and October 2017 were postoperative recurrence, and consequently, a substantial propor- tion of patients operated for breast cancer LM undergo futile and included in the study. This resulted in 36 patients with a median possibly even detrimental surgery. Accordingly, the role of surgery follow-up of 10.7 years (Table 1). A total of 175 slides were for treatment of breast cancer LM remains largely debated . evaluated for the LM from these 36 patients (median=4and In large retrospective studies, the histopathological growth average= 4.9, Supplementary Fig. 1). The distribution of the patterns (HGPs) of resected LM of patients with colorectal cancer percentages of the R-HGP and D-HGP components are represented predict the postoperative outcome, clearly surpassing the prog- per patient in Supplementary Fig. 2a. Of note, we did not observe a 7–9 nostic power of the traditional clinical risk scores .HGPsare correlation between the number of slides that were evaluated per identified by light microscopy in standard hematoxylin-and-eosin- patient and the percentage of R-HGP (Supplementary Fig. 2b). For stained (H&E) tissue sections at the interface between the tumor 11 patients, the HGPs were evaluated in multiple metastases. In and the liver (Fig. 1a, b). International consensus guidelines for HGP agreement with what has already been reported in LM from scoring have been established, allowing reproducible and accurate patients with colorectal cancer , we observed a low intra-patient assessment of the HGP of LM. Due to the heterogeneity of the inter-metastasis heterogeneity with regard to the HGP (Supple- HGP within a metastasis, this can only be reliably assessed on mentary Fig. 3). We further categorized the LM based on their HGP surgical resection specimen and not on core needle biopsies. In the for the remaining analyses: (1) LM with a pure replacement HGP (i.e. replacement pattern (R-HGP), cancer cells infiltrate the hepatic present in 100% of the tumor–liver interface in all the available plates and replace the resident hepatocytes, thereby co-opting the sections), further referred to as “pure R-HGP” and present in sinusoidal blood vessels of the liver. In metastases with a 16 patients (44%) and (2) LM that are at least partly (1% of interface 1 2 Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Translational Cancer Research Unit, GZA Hospitals & CORE, MIPRO, University of 3 4 Antwerp, Antwerp, Belgium. Department of Oncological Research, Oncology Center, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium. Department of Abdominal Surgery, Hôpital Erasme, Université Libre de Bruxelles, Institut Jules Bordet, 6 7 Université Libre de Bruxelles, Brussels, Belgium. Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Clinical Trials Conduct Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Breast Cancer Translational Lab, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 9 10 Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, 11 12 Brussels, Belgium. Department of Clinical Sciences and Community Health & DSRC, University of Milan, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. These authors contributed equally: Ali Bohlok, Peter Vermeulen, Christine Desmedt, Vincent Donckier. email: christine.desmedt@kuleuven.be; vincent.donckier@bordet.be Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Bohlok et al. Fig. 1 Histological growth patterns in liver metastases from breast cancer patients. a Breast cancer LM with a desmoplastic growth pattern (H&E staining): black double-headed arrows indicate the desmoplastic rim that separates the tumor tissue from the liver parenchyma. b Breast cancer liver metastasis with a replacement growth pattern (H&E staining): the white arrows indicate some of the regions where cancer cells grow into the liver cell plates and replace the hepatocytes. Cancer cells are in contact with the hepatocytes. The yellow asterisks mark two co- opted sinusoidal blood vessels. c Kaplan–Meier curves displaying the PFS probability according to the HGP group. d Kaplan–Meier curves displaying the OS probability according to the HGP group. e Univariate and multivariate Cox regression analyses for PFS. f Univariate and multivariate Cox regression analyses for OS. CI confidence interval, HGP histological growth pattern (D desmoplastic, R replacement), H&E hematoxylin and eosin, LM liver metastasi(e)s, PFS progression-free survival, OS overall survival. or more) desmoplastic, further referred to as “any D-HGP” and In 33% of the patients (10/30), the ER status differed between the present in the remaining 20 patients (56%). primary tumor and LM. In 8 patients, ER expression was lost in the There was no association between these HGP categories and LM, while in 2 patients the LM gained ER expression. Significantly estrogen receptor (ER) or HER2 status of the primary breast more patients in the “pure R-HGP” group had a primary tumor carcinoma or of the LM (Table 1). LM subtypes were as follows: 7 associated with lymph node metastases (79 versus 44% in the ER−/HER2− (19%), 12 HER2+ (33%), and 17 ER+/HER2− (47%). “any D-HGP” group; p = 0.02). npj Breast Cancer (2020) 64 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Bohlok et al. Table 1. Patient and sample characteristics according to the histological growth pattern present in the liver metastasi(e)s. Pure R-HGP Any D-HGP p (Fisher) Menopausal status at primary diagnosis Pre 6 (40.0) 13 (76.5) 0.070 Post 9 (60.0) 4 (23.5) Missing 1 3 Age at primary diagnosis ≤50 6 (37.5) 12 (60.0) 0.315 >50 10 (62.5) 8 (40.0) TNM_T 0 0 (0.0) 1 (6.2) 0.172 1 6 (46.2) 10 (62.5) 2 6 (46.2) 3 (18.8) 3 0 (0.0) 2 (12.5) 4 1 (7.7) 0 (0.0) Missing 3 4 TNM_N 0 3 (21.4) 10 (55.6) 0.020 1 8 (57.1) 2 (11.1) 2 3 (21.4) 6 (33.3) Missing 2 2 TNM_M 0 9 (56.2) 14 (70.0) 0.493 1 7 (43.8) 6 (30.0) Grade (primary) 1 5 (35.7) 2 (12.5) 0.356 2 5 (35.7) 9 (56.2) 3 4 (28.6) 5 (31.2) Missing 2 4 ER status (primary) Negative 3 (21.4) 2 (12.5) 0.642 Positive 11 (78.6) 14 (87.5) Missing 2 4 PgR status (primary) Negative 6 (42.9) 5 (31.2) 0.707 Positive 8 (57.1) 11 (68.8) Missing 2 4 HER2 status (primary) Negative 8 (61.5) 10 (62.5) 1 Positive 5 (38.5) 6 (37.5) Missing 3 4 Histological type (primary) IDC (NST) 12 (75.0) 16 (88.9) 0.410 ILC 2 (12.5) 2 (11.1) Other 2 (12.5) 0 (0.0) Missing 0 2 Neoadjuvant chemotherapy No 7 (43.8) 13 (76.5) 0.080 Yes 9 (56.2) 4 (23.5) Missing 0 3 Menopausal status at metastatic diagnosis Pre 4 (28.6) 6 (35.3) 1 Post 10 (71.4) 11 (64.7) Missing 2 3 Age at metastatic diagnosis ≤50 6 (37.5) 9 (45.0) 0.741 >50 10 (62.5) 11 (55.0) ER status (met.) Negative 6 (37.5) 7 (35.0) 1 Positive 10 (62.5) 13 (65.0) PgR status (met.) Negative 7 (43.8) 12 (60.0) 0.503 Positive 9 (56.2) 8 (40.0) HER2 status (met.) Negative 11 (68.8) 13 (65.0) 1 Positive 5 (31.2) 7 (35.0) Nr hepatic met. lesions (preop.) 1 8 (50.0) 11 (55.0) 1 >1 8 (50.0) 9 (45.0) Extra hepatic met. No 12 (75.0) 16 (80.0) 1 Yes 4 (25.0) 4 (20.0) Interval primary/met. (years) <1 year 6 (37.5) 3 (15.0) 0.300 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2020) 64 A. Bohlok et al. Table 1 continued Pure R-HGP Any D-HGP p (Fisher) 1–5 years 5 (31.2) 10 (50.0) >5 years 5 (31.2) 7 (35.0) ER status (P→ LM) Gain ER 1 (7.1) 1 (6.2) 0.934 Loss ER 3 (21.4) 5 (31.2) Stable ER− 2 (14.3) 1 (6.2) Stable ER+ 8 (57.1) 9 (56.2) Missing 2 4 PgR status (P→ LM) Gain PgR 3 (21.4) 1 (6.2) 0.622 Loss PgR 3 (21.4) 6 (37.5) Stable PgR− 3 (21.4) 4 (25.0) Stable PgR+ 5 (35.7) 5 (31.2) Missing 2 4 HER2 status (P→ LM) Gain HER2 1 (7.7) 1 (6.2) 1 Loss HER2 2 (15.4) 2 (12.5) Stable HER2− 7 (53.8) 9 (56.2) Stable HER2+ 3 (23.1) 4 (25.0) Missing 3 4 Size largest lesion <50 mm 13 (81.2) 18 (90.0) 0.637 ≥50 mm 3 (18.8) 2 (10.0) Preoperative systemic treatment No 1 (6.2) 1 (5.9) 1 Yes 15 (93.8) 16 (94.1) Missing 0 3 ER estrogen receptor, HGP histological growth pattern (D desmoplastic, R replacement), IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, LM liver metastasis, NST invasive carcinoma of no special type, P primary tumor, PgR progesterone receptor, TNM tumor–node–metastasis staging system. “Any D-HGP” was independently associated with better PFS there is a strong need for the molecular characterization of LM after liver surgery when compared with “pure R-HGP” (adjusted from breast cancer patients beyond the need for markers to guide hazard ratio (HR) = 0.24, 95% confidence interval (CI): 0.08–0.70; the surgical decision. For instance, recent reports have suggested p = 0.009, Fig. 1c, e). All patients of the “pure R-HGP” group that immunotherapy based on checkpoint inhibition is less relapsed within the first 20 months after liver surgery. Similarly, efficient in metastatic cancer patients with LM . Although more improved overall survival (OS) was observed for patients with “any studies are needed to evaluate the immune context in LM, this D-HGP” LM as compared to patients with “pure R-HGP” metastases clinical observation could be related to the fact that LM with the (adjusted HR = 0.20, 95% CI: 0.05–0.80; p = 0.023, Fig. 1d, f). D-HGP generally present the so-called immune-excluded pheno- 15,16 In this study, we addressed whether the HGP has a potential to type and LM with the R-HGP the immune-desert phenotype , predict outcome in breast cancer patients undergoing surgical as illustrated in Supplementary Fig. 5. Altogether, this study resection of LM. A first relevant finding is that a high fraction of emphasizes the need for studying LM from breast cancer patients in more detail to allow further personalization of local and these patients (44%) have LM with a pure R-HGP, whereas systemic treatment for these patients in the near future. this pattern is only observed in 4–20% of the resected colorectal 7–9 LM . This indicates that the presence of the distinct HGPs may depend on the type of primary tumor. Comparable to what has 7–9 12 METHODS been described for colorectal cancer and uveal melanoma ,we Scoring of the HGPs confirm the association between R-HGP and poor outcome after resection of LM. In contrast, D-HGP may thus identify breast The HGP of the LM was scored according to the international guidelines by an experienced pathologist (P.V.) blinded to the outcome data. All cancer patients who can be offered (repeated) hepatic surgery to available H&E sections of all metastases were scored for each patient. The prolong survival. In this series, all patients with pure R-HGP LM entire tumor–liver interface was evaluated for each tissue section. The HGP rapidly relapsed within 2 years after surgery, indicating a more was scored as a relative proportion (percentage) of the interface in which aggressive disease course and strongly questioning the role of each of the HGPs (replacement or desmoplastic) occurred. Average HGP surgery in these cases. If these results are confirmed in larger scores were then calculated for each patient. Of note, we reported series, HGP assessment could be implemented in studies to test previously a high interobserver agreement for scoring HGP . patient-tailored management of LM. Furthermore, if HGP could be predicted preoperatively, for example, by using dedicated medical Statistical analyses imaging methods since it cannot be assessed on biopsies, it may Clinical and pathological data were derived from the electronic patient represent a new factor for guiding the surgical decision in breast files. Associations between HGP and clinicopathological characteristics cancer patients with resectable LM. While D-HGP and R-HGP could were assessed with Fisher exact test. Associations with PFS and OS were present different radiological features, namely, at tumor–liver assessed with Cox proportional hazard regression considering date of interface (see Supplementary Figs. 3 and 4 as an example), hepatic surgery as the starting time point, after assessing the proportional prospectively designed radiomics studies are needed to ensure hazard assumptions. There were 29 and 20 events observed for PFS and adequate sensitivity and specificity of this approach . Finally, OS, respectively. Age at hepatic surgery and ER and HER2 status of the LM npj Breast Cancer (2020) 64 Published in partnership with the Breast Cancer Research Foundation A. Bohlok et al. as well as the presence of extra-hepatic metastases were considered as 15. Stremitzer, S. et al. Immune phenotype and histopathological growth pattern in adjustment variables and center as stratification factor. patients with colorectal liver metastases. Br. J. Cancer 122, 1518–1524 (2020). 16. Höppener, D. J. et al. Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis. Br. J. Cancer 123, 196–206 Ethics approval (2020). This study was approved by the ethical committee of both institutions 17. Höppener, D. J. et al. Histopathological growth patterns of colorectal liver (CE2953 on 5 March 2019 for Institut Bordet and P2019/232/NA on 4 April metastasis exhibit little heterogeneity and can be determined with a high 2019 for the Hôpital Erasme) and the necessity for written informed diagnostic accuracy. Clin. Exp. Metastasis https://doi.org/10.1007/s10585-019- consent was waived given the retrospective nature of the study. 09975-0 (2019). 18. Bohlok, A. et al. Metadata supporting the published article: Association between the histopathological growth patterns of liver metastases and survival after Reporting summary hepatic surgery in breast cancer patients. Figshare. https://doi.org/10.6084/m9. Further information on research design is available in the Nature Research figshare.13177307 (2020). Reporting Summary linked to this article. ACKNOWLEDGEMENTS DATA AVAILABILITY This work has been funded by “Le Fonds Ithier”, the King Baudouin Foundation, and The datasets that support the findings of this study are not publicly available but will “Les Amis de Bordet”. The funders had no role in the design of the study; the be made available upon reasonable request, following ethics committee approval collection, analysis, or interpretation of the data; the writing of the manuscript; or the and a data transfer agreement, to guarantee the General Data Protection Regulation, decision to submit the manuscript for publication. F.R. is supported by the Fondation as described in the following metadata record: https://doi.org/10.6084/m9. Cancer Luxemburg. figshare.13177307. Please contact the corresponding author, V.D. (email address: vincent.donckier@bordet.be) to request access to the data. AUTHOR CONTRIBUTIONS Received: 3 June 2020; Accepted: 12 November 2020; Study concept and design, drafting of the manuscript, and study supervision: P.V., C.D., and V.D. P.V., A.B., F.R., V.D., and C.D. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition, analysis, or interpretation of data and critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: F.R. and E.B. Obtained REFERENCES funding: A.H. and V.D. C.D. and V.D. are joint senior authors . 1. Kwapisz, D. Oligometastatic breast cancer. Breast Cancer 26, 138–146 (2019). 2. Sledge, G. W. Curing metastatic breast cancer. J. Oncol. Pract. 12,6–10 (2016). 3. Sabel, M. & White, J. The role of local therapies in metastatic breast cancer. COMPETING INTERESTS https://www.uptodate.com/contents/the-role-of-local-therapies-in-metastatic- The authors declare no competing interests. breast-cancer (2020). 4. Westphal, T., Gampenrieder, S. P., Rinnerthaler, G. & Greil, R. Cure in metastatic breast cancer. Memo 11, 172–179 (2018). ADDITIONAL INFORMATION 5. Cardoso, F. et al. 4th ESO-ESMO international consensus guidelines for advanced Supplementary information is available for this paper at https://doi.org/10.1038/ breast cancer (ABC 4). Ann. Oncol. 29, 1634–1657 (2018). s41523-020-00209-1. 6. Golse, N. & Adam, R. Liver metastases from breast cancer: what role for surgery? Indications and results. Clin. Breast Cancer 17, 256–265 (2017). Correspondence and requests for materials should be addressed to C.D. or V.D. 7. Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016). Reprints and permission information is available at http://www.nature.com/ 8. Galjart, B. et al. Angiogenic desmoplastic histopathological growth pattern as a reprints prognostic marker of good outcome in patients with colorectal liver metastases. Angiogenesis 22, 355–368 (2019). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 9. Fernández Moro, C., Bozóky, B. & Gerling, M. Growth patterns of colorectal cancer in published maps and institutional affiliations. liver metastases and their impact on prognosis: a systematic review. BMJ Open Gastroenterol. 5, e000217 (2018). 10. van Dam, P.-J. et al. International consensus guidelines for scoring the histo- pathological growth patterns of liver metastasis. Br. J. Cancer 117, 1427–1441 (2017). Open Access This article is licensed under a Creative Commons 11. Höppener, D. J. et al. The disease-free interval between resection of primary Attribution 4.0 International License, which permits use, sharing, colorectal malignancy and the detection of hepatic metastases predicts disease adaptation, distribution and reproduction in any medium or format, as long as you give recurrence but not overall survival. Ann. Surg. Oncol. https://doi.org/10.1245/ appropriate credit to the original author(s) and the source, provide a link to the Creative s10434-019-07481-x (2019). Commons license, and indicate if changes were made. The images or other third party 12. Barnhill, R. et al. Replacement and desmoplastic histopathological growth pat- material in this article are included in the article’s Creative Commons license, unless terns: a pilot study of prediction of outcome in patients with uveal melanoma indicated otherwise in a credit line to the material. If material is not included in the liver metastases. J. Pathol. Clin. Res. 4, 227–240 (2018). article’s Creative Commons license and your intended use is not permitted by statutory 13. Cheng, J. et al. Prediction of histopathologic growth patterns of colorectal liver regulation or exceeds the permitted use, you will need to obtain permission directly metastases with a noninvasive imaging method. Ann. Surg. Oncol. 26, 4587–4598 from the copyright holder. To view a copy of this license, visit http://creativecommons. (2019). org/licenses/by/4.0/. 14. Bilen, M. A. et al. Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 19, 857 (2019). © The Author(s) 2020 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2020) 64 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

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  • GW Sledge (2016)

    6

    J. Oncol. Pract., 12

  • D Kwapisz (2019)

    138

    Breast Cancer, 26

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Abstract

www.nature.com/npjbcancer BRIEF COMMUNICATION OPEN Association between the histopathological growth patterns of liver metastases and survival after hepatic surgery in breast cancer patients 1,13 2,3,13 4 2 3 4 4 Ali Bohlok , Peter Vermeulen , Sophia Leduc , Emily Latacz , Lara Botzenhart , François Richard , Maxim De Schepper , 4 5 6 7 8 6 9 Tatjana Geukens , Valerio Lucidi , Michail Ignatiadis , Philippe Aftimos , Christos Sotiriou , Martine Piccart , Alain Hendlisz , 2 2,3 10 11 12 4,13 Steven Van Laere , Luc Dirix , Jean-Christophe Noël , Elia Biganzoli , Denis Larsimont , Christine Desmedt and 1,13 Vincent Donckier Currently, there are no markers to identify patients with liver-only or liver-dominant metastases that would benefit from hepatic surgery. Here we characterized histopathological growth patterns (HGPs) of liver metastases in a consecutive series of 36 breast cancer patients who underwent hepatic surgery. Survival analyses showed that the presence of a desmoplastic HGP in the liver metastases (a rim of fibrous tissue separating cancer cells from the liver parenchyma, present in 20 (56%) patients) is independently associated with favorable progression-free and overall survival when compared with the replacement HGP (cancer cells growing into the liver parenchyma, present in 16 (44%) patients). npj Breast Cancer (2020) 6:64 ; https://doi.org/10.1038/s41523-020-00209-1 Even if metastatic breast cancer is frequently considered as a desmoplastic pattern (D-HGP), cancer cells are separated from liver systemic disease, local treatment targeting metastases may result cells by a rim of desmoplastic stroma, which is often densely 1–4 in prolonged survival in selected cases . In particular, in patients infiltrated with inflammatory cells. In the D-HGP, tumor vasculariza- with liver-only or liver-dominant metastases, surgical resection of tion is provided by angiogenesis. In colorectal patients undergoing liver metastases (LM) is associated with survival between 22 and resection of LM, the R-HGP is associated with worse postoperative 7–9 61 months and long-term progression-free survival (PFS) in survival as compared to D-HGP LM . Here we aimed at scoring selected cases , serving as a proof of concept for an oligometa- and evaluating the prognostic value of HGP in patients with breast static status in a subgroup of patients. At present, however, there cancer undergoing resection of LM. Consecutive patients with breast cancer who underwent surgical are no established biomarkers to identify this subgroup . resection for LM at the Institut Jules Bordet and the Hôpital Erasme Furthermore, no factor has been reliably associated with rapid (Brussels, Belgium) between April 2000 and October 2017 were postoperative recurrence, and consequently, a substantial propor- tion of patients operated for breast cancer LM undergo futile and included in the study. This resulted in 36 patients with a median possibly even detrimental surgery. Accordingly, the role of surgery follow-up of 10.7 years (Table 1). A total of 175 slides were for treatment of breast cancer LM remains largely debated . evaluated for the LM from these 36 patients (median=4and In large retrospective studies, the histopathological growth average= 4.9, Supplementary Fig. 1). The distribution of the patterns (HGPs) of resected LM of patients with colorectal cancer percentages of the R-HGP and D-HGP components are represented predict the postoperative outcome, clearly surpassing the prog- per patient in Supplementary Fig. 2a. Of note, we did not observe a 7–9 nostic power of the traditional clinical risk scores .HGPsare correlation between the number of slides that were evaluated per identified by light microscopy in standard hematoxylin-and-eosin- patient and the percentage of R-HGP (Supplementary Fig. 2b). For stained (H&E) tissue sections at the interface between the tumor 11 patients, the HGPs were evaluated in multiple metastases. In and the liver (Fig. 1a, b). International consensus guidelines for HGP agreement with what has already been reported in LM from scoring have been established, allowing reproducible and accurate patients with colorectal cancer , we observed a low intra-patient assessment of the HGP of LM. Due to the heterogeneity of the inter-metastasis heterogeneity with regard to the HGP (Supple- HGP within a metastasis, this can only be reliably assessed on mentary Fig. 3). We further categorized the LM based on their HGP surgical resection specimen and not on core needle biopsies. In the for the remaining analyses: (1) LM with a pure replacement HGP (i.e. replacement pattern (R-HGP), cancer cells infiltrate the hepatic present in 100% of the tumor–liver interface in all the available plates and replace the resident hepatocytes, thereby co-opting the sections), further referred to as “pure R-HGP” and present in sinusoidal blood vessels of the liver. In metastases with a 16 patients (44%) and (2) LM that are at least partly (1% of interface 1 2 Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Translational Cancer Research Unit, GZA Hospitals & CORE, MIPRO, University of 3 4 Antwerp, Antwerp, Belgium. Department of Oncological Research, Oncology Center, GZA Hospitals Sint-Augustinus, Antwerp, Belgium. Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium. Department of Abdominal Surgery, Hôpital Erasme, Université Libre de Bruxelles, Institut Jules Bordet, 6 7 Université Libre de Bruxelles, Brussels, Belgium. Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Clinical Trials Conduct Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Breast Cancer Translational Lab, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 9 10 Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, 11 12 Brussels, Belgium. Department of Clinical Sciences and Community Health & DSRC, University of Milan, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. These authors contributed equally: Ali Bohlok, Peter Vermeulen, Christine Desmedt, Vincent Donckier. email: christine.desmedt@kuleuven.be; vincent.donckier@bordet.be Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Bohlok et al. Fig. 1 Histological growth patterns in liver metastases from breast cancer patients. a Breast cancer LM with a desmoplastic growth pattern (H&E staining): black double-headed arrows indicate the desmoplastic rim that separates the tumor tissue from the liver parenchyma. b Breast cancer liver metastasis with a replacement growth pattern (H&E staining): the white arrows indicate some of the regions where cancer cells grow into the liver cell plates and replace the hepatocytes. Cancer cells are in contact with the hepatocytes. The yellow asterisks mark two co- opted sinusoidal blood vessels. c Kaplan–Meier curves displaying the PFS probability according to the HGP group. d Kaplan–Meier curves displaying the OS probability according to the HGP group. e Univariate and multivariate Cox regression analyses for PFS. f Univariate and multivariate Cox regression analyses for OS. CI confidence interval, HGP histological growth pattern (D desmoplastic, R replacement), H&E hematoxylin and eosin, LM liver metastasi(e)s, PFS progression-free survival, OS overall survival. or more) desmoplastic, further referred to as “any D-HGP” and In 33% of the patients (10/30), the ER status differed between the present in the remaining 20 patients (56%). primary tumor and LM. In 8 patients, ER expression was lost in the There was no association between these HGP categories and LM, while in 2 patients the LM gained ER expression. Significantly estrogen receptor (ER) or HER2 status of the primary breast more patients in the “pure R-HGP” group had a primary tumor carcinoma or of the LM (Table 1). LM subtypes were as follows: 7 associated with lymph node metastases (79 versus 44% in the ER−/HER2− (19%), 12 HER2+ (33%), and 17 ER+/HER2− (47%). “any D-HGP” group; p = 0.02). npj Breast Cancer (2020) 64 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A. Bohlok et al. Table 1. Patient and sample characteristics according to the histological growth pattern present in the liver metastasi(e)s. Pure R-HGP Any D-HGP p (Fisher) Menopausal status at primary diagnosis Pre 6 (40.0) 13 (76.5) 0.070 Post 9 (60.0) 4 (23.5) Missing 1 3 Age at primary diagnosis ≤50 6 (37.5) 12 (60.0) 0.315 >50 10 (62.5) 8 (40.0) TNM_T 0 0 (0.0) 1 (6.2) 0.172 1 6 (46.2) 10 (62.5) 2 6 (46.2) 3 (18.8) 3 0 (0.0) 2 (12.5) 4 1 (7.7) 0 (0.0) Missing 3 4 TNM_N 0 3 (21.4) 10 (55.6) 0.020 1 8 (57.1) 2 (11.1) 2 3 (21.4) 6 (33.3) Missing 2 2 TNM_M 0 9 (56.2) 14 (70.0) 0.493 1 7 (43.8) 6 (30.0) Grade (primary) 1 5 (35.7) 2 (12.5) 0.356 2 5 (35.7) 9 (56.2) 3 4 (28.6) 5 (31.2) Missing 2 4 ER status (primary) Negative 3 (21.4) 2 (12.5) 0.642 Positive 11 (78.6) 14 (87.5) Missing 2 4 PgR status (primary) Negative 6 (42.9) 5 (31.2) 0.707 Positive 8 (57.1) 11 (68.8) Missing 2 4 HER2 status (primary) Negative 8 (61.5) 10 (62.5) 1 Positive 5 (38.5) 6 (37.5) Missing 3 4 Histological type (primary) IDC (NST) 12 (75.0) 16 (88.9) 0.410 ILC 2 (12.5) 2 (11.1) Other 2 (12.5) 0 (0.0) Missing 0 2 Neoadjuvant chemotherapy No 7 (43.8) 13 (76.5) 0.080 Yes 9 (56.2) 4 (23.5) Missing 0 3 Menopausal status at metastatic diagnosis Pre 4 (28.6) 6 (35.3) 1 Post 10 (71.4) 11 (64.7) Missing 2 3 Age at metastatic diagnosis ≤50 6 (37.5) 9 (45.0) 0.741 >50 10 (62.5) 11 (55.0) ER status (met.) Negative 6 (37.5) 7 (35.0) 1 Positive 10 (62.5) 13 (65.0) PgR status (met.) Negative 7 (43.8) 12 (60.0) 0.503 Positive 9 (56.2) 8 (40.0) HER2 status (met.) Negative 11 (68.8) 13 (65.0) 1 Positive 5 (31.2) 7 (35.0) Nr hepatic met. lesions (preop.) 1 8 (50.0) 11 (55.0) 1 >1 8 (50.0) 9 (45.0) Extra hepatic met. No 12 (75.0) 16 (80.0) 1 Yes 4 (25.0) 4 (20.0) Interval primary/met. (years) <1 year 6 (37.5) 3 (15.0) 0.300 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2020) 64 A. Bohlok et al. Table 1 continued Pure R-HGP Any D-HGP p (Fisher) 1–5 years 5 (31.2) 10 (50.0) >5 years 5 (31.2) 7 (35.0) ER status (P→ LM) Gain ER 1 (7.1) 1 (6.2) 0.934 Loss ER 3 (21.4) 5 (31.2) Stable ER− 2 (14.3) 1 (6.2) Stable ER+ 8 (57.1) 9 (56.2) Missing 2 4 PgR status (P→ LM) Gain PgR 3 (21.4) 1 (6.2) 0.622 Loss PgR 3 (21.4) 6 (37.5) Stable PgR− 3 (21.4) 4 (25.0) Stable PgR+ 5 (35.7) 5 (31.2) Missing 2 4 HER2 status (P→ LM) Gain HER2 1 (7.7) 1 (6.2) 1 Loss HER2 2 (15.4) 2 (12.5) Stable HER2− 7 (53.8) 9 (56.2) Stable HER2+ 3 (23.1) 4 (25.0) Missing 3 4 Size largest lesion <50 mm 13 (81.2) 18 (90.0) 0.637 ≥50 mm 3 (18.8) 2 (10.0) Preoperative systemic treatment No 1 (6.2) 1 (5.9) 1 Yes 15 (93.8) 16 (94.1) Missing 0 3 ER estrogen receptor, HGP histological growth pattern (D desmoplastic, R replacement), IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, LM liver metastasis, NST invasive carcinoma of no special type, P primary tumor, PgR progesterone receptor, TNM tumor–node–metastasis staging system. “Any D-HGP” was independently associated with better PFS there is a strong need for the molecular characterization of LM after liver surgery when compared with “pure R-HGP” (adjusted from breast cancer patients beyond the need for markers to guide hazard ratio (HR) = 0.24, 95% confidence interval (CI): 0.08–0.70; the surgical decision. For instance, recent reports have suggested p = 0.009, Fig. 1c, e). All patients of the “pure R-HGP” group that immunotherapy based on checkpoint inhibition is less relapsed within the first 20 months after liver surgery. Similarly, efficient in metastatic cancer patients with LM . Although more improved overall survival (OS) was observed for patients with “any studies are needed to evaluate the immune context in LM, this D-HGP” LM as compared to patients with “pure R-HGP” metastases clinical observation could be related to the fact that LM with the (adjusted HR = 0.20, 95% CI: 0.05–0.80; p = 0.023, Fig. 1d, f). D-HGP generally present the so-called immune-excluded pheno- 15,16 In this study, we addressed whether the HGP has a potential to type and LM with the R-HGP the immune-desert phenotype , predict outcome in breast cancer patients undergoing surgical as illustrated in Supplementary Fig. 5. Altogether, this study resection of LM. A first relevant finding is that a high fraction of emphasizes the need for studying LM from breast cancer patients in more detail to allow further personalization of local and these patients (44%) have LM with a pure R-HGP, whereas systemic treatment for these patients in the near future. this pattern is only observed in 4–20% of the resected colorectal 7–9 LM . This indicates that the presence of the distinct HGPs may depend on the type of primary tumor. Comparable to what has 7–9 12 METHODS been described for colorectal cancer and uveal melanoma ,we Scoring of the HGPs confirm the association between R-HGP and poor outcome after resection of LM. In contrast, D-HGP may thus identify breast The HGP of the LM was scored according to the international guidelines by an experienced pathologist (P.V.) blinded to the outcome data. All cancer patients who can be offered (repeated) hepatic surgery to available H&E sections of all metastases were scored for each patient. The prolong survival. In this series, all patients with pure R-HGP LM entire tumor–liver interface was evaluated for each tissue section. The HGP rapidly relapsed within 2 years after surgery, indicating a more was scored as a relative proportion (percentage) of the interface in which aggressive disease course and strongly questioning the role of each of the HGPs (replacement or desmoplastic) occurred. Average HGP surgery in these cases. If these results are confirmed in larger scores were then calculated for each patient. Of note, we reported series, HGP assessment could be implemented in studies to test previously a high interobserver agreement for scoring HGP . patient-tailored management of LM. Furthermore, if HGP could be predicted preoperatively, for example, by using dedicated medical Statistical analyses imaging methods since it cannot be assessed on biopsies, it may Clinical and pathological data were derived from the electronic patient represent a new factor for guiding the surgical decision in breast files. Associations between HGP and clinicopathological characteristics cancer patients with resectable LM. While D-HGP and R-HGP could were assessed with Fisher exact test. Associations with PFS and OS were present different radiological features, namely, at tumor–liver assessed with Cox proportional hazard regression considering date of interface (see Supplementary Figs. 3 and 4 as an example), hepatic surgery as the starting time point, after assessing the proportional prospectively designed radiomics studies are needed to ensure hazard assumptions. There were 29 and 20 events observed for PFS and adequate sensitivity and specificity of this approach . Finally, OS, respectively. Age at hepatic surgery and ER and HER2 status of the LM npj Breast Cancer (2020) 64 Published in partnership with the Breast Cancer Research Foundation A. Bohlok et al. as well as the presence of extra-hepatic metastases were considered as 15. Stremitzer, S. et al. Immune phenotype and histopathological growth pattern in adjustment variables and center as stratification factor. patients with colorectal liver metastases. Br. J. Cancer 122, 1518–1524 (2020). 16. Höppener, D. J. et al. Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis. Br. J. Cancer 123, 196–206 Ethics approval (2020). This study was approved by the ethical committee of both institutions 17. Höppener, D. J. et al. Histopathological growth patterns of colorectal liver (CE2953 on 5 March 2019 for Institut Bordet and P2019/232/NA on 4 April metastasis exhibit little heterogeneity and can be determined with a high 2019 for the Hôpital Erasme) and the necessity for written informed diagnostic accuracy. Clin. Exp. Metastasis https://doi.org/10.1007/s10585-019- consent was waived given the retrospective nature of the study. 09975-0 (2019). 18. Bohlok, A. et al. Metadata supporting the published article: Association between the histopathological growth patterns of liver metastases and survival after Reporting summary hepatic surgery in breast cancer patients. Figshare. https://doi.org/10.6084/m9. Further information on research design is available in the Nature Research figshare.13177307 (2020). Reporting Summary linked to this article. ACKNOWLEDGEMENTS DATA AVAILABILITY This work has been funded by “Le Fonds Ithier”, the King Baudouin Foundation, and The datasets that support the findings of this study are not publicly available but will “Les Amis de Bordet”. The funders had no role in the design of the study; the be made available upon reasonable request, following ethics committee approval collection, analysis, or interpretation of the data; the writing of the manuscript; or the and a data transfer agreement, to guarantee the General Data Protection Regulation, decision to submit the manuscript for publication. F.R. is supported by the Fondation as described in the following metadata record: https://doi.org/10.6084/m9. Cancer Luxemburg. figshare.13177307. Please contact the corresponding author, V.D. (email address: vincent.donckier@bordet.be) to request access to the data. AUTHOR CONTRIBUTIONS Received: 3 June 2020; Accepted: 12 November 2020; Study concept and design, drafting of the manuscript, and study supervision: P.V., C.D., and V.D. P.V., A.B., F.R., V.D., and C.D. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition, analysis, or interpretation of data and critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: F.R. and E.B. Obtained REFERENCES funding: A.H. and V.D. C.D. and V.D. are joint senior authors . 1. Kwapisz, D. Oligometastatic breast cancer. Breast Cancer 26, 138–146 (2019). 2. Sledge, G. W. Curing metastatic breast cancer. J. Oncol. Pract. 12,6–10 (2016). 3. Sabel, M. & White, J. The role of local therapies in metastatic breast cancer. 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