Clinicopathological characteristics and survival outcomes in patients with synchronous lung metastases upon initial metastatic breast cancer diagnosis in Han population

Chia sẻ: _ _ | Ngày: | Loại File: PDF | Số trang:9

Thêm vào BST

Báo xấu

12
lượt xem 2
download

Download Vui lòng tải xuống để xem tài liệu đầy đủ

We investigated the clinicopathological characteristics and survival of breast cancer lung metastases (BCLM) patients at initial diagnosis of metastatic breast cancer (MBC) in the Han population.

Chủ đề:

Bình luận(0) Đăng nhập để gửi bình luận!

Lưu

Nội dung Text: Clinicopathological characteristics and survival outcomes in patients with synchronous lung metastases upon initial metastatic breast cancer diagnosis in Han population

Lin et al. BMC Cancer (2021) 21:1330 https://doi.org/10.1186/s12885-021-09038-2 RESEARCH Open Access Clinicopathological characteristics and survival outcomes in patients with synchronous lung metastases upon initial metastatic breast cancer diagnosis in Han population Shaoyan Lin, Hongnan Mo, Yiqun Li, Xiuwen Guan, Yimeng Chen, Zijing Wang and Binghe Xu* Abstract Background: We investigated the clinicopathological characteristics and survival of breast cancer lung metastases (BCLM) patients at initial diagnosis of metastatic breast cancer (MBC) in the Han population. Methods: We attained clinical data of 3155 MBC patients initially diagnosed between April 2000 and September 2019 from the China National Cancer Center and finally included 2263 MBC patients in this study, among which 809 patients presented with lung metastases at first MBC diagnosis. The risk factors for BCLM were determined using multivariate logistic regression analysis and the prognostic factors of BCLM patients were assessed by univariate and multivariate Cox regression analyses. Results: Patients with triple-negative subtype (42.3%) harbored the highest incidence proportions of lung metas- tases. Age ≥ 50 years, Eastern Cooperative Oncology Group (ECOG) 2, M1, hormone receptor-negative (HR-)/human epidermal growth factor receptor 2-positive (HER2) + subtype, triple-negative subtype and disease-free survival (DFS) > 2 years were remarkably associated with higher incidence of lung metastases, while invasive lobular carci- noma (ILC) and bone metastases were significantly correlated with lower odds of lung metastases at diagnosis. The median survival of BCLM patients was 41.7 months, with triple-negative subtype experiencing the worst prognosis of 26.8 months. ECOG 2, triple-negative subtype, liver metastases, multi-metastatic sites and DFS ≤ 2 years were signifi- cantly correlated with poor survival of BCLM patients. Conclusions: Our study provides essential information on clinicopathological features and survival outcomes of BCLM patients at initial diagnosis of MBC in China. Keywords: Breast neoplasms, Lung, Neoplasm metastasis, Prognosis, Survival Background Lung metastasis is the second most frequent distant metastases of breast cancer [1, 2], clinically presenting *Correspondence: xubinghe@medmail.com.cn in 15–25% of metastatic breast cancer (MBC) patients Department of Medical Oncology, National Cancer Center/National [3, 4]. Autopsy data of 197 women dying with MBC over Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy a period of 50 years revealed that 80.7% of patients had of Medical Sciences & Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China lung or pleura metastases [5]. A population-based study © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Lin et al. BMC Cancer (2021) 21:1330 Page 2 of 9 indicated that the median survival of 3372 patients with proven. Based on the guidelines in our center, lung biopsy lung metastases at primary breast cancer diagnosis was was not essential unless the imaging was uncertain. With 21 months [6]. Although the prognosis of MBC patients the improvement of the guidelines, lung biopsy was also with metastases confined to lungs is not so poor as considerable for the sake of therapy guidance or patient brains or livers [7], most patients are considered incur- wishes. Telephone calls or clinical visits were used to fol- able and the treatment is still intractable. With an occult low up patients further to June 30, 2019 or date of their onset, lung metastases from breast cancer usually pre- deaths. sent asymptomatically and progress aggressively with- out appropriate care [8]. Systemic treatments including Study variables chemotherapy, targeted therapy and hormone therapy Study variables, including age at initial MBC diagnosis, are recommended for patients with breast cancer lung Eastern Cooperative Oncology Group (ECOG) grade, metastases (BCLM) [9] and pulmonary metastasectomy pathological type, TNM stage of primary breast can- is considerable for properly selected cases [10]. The early cer, tumor receptor status, number and type of meta- detection of lung metastasis and the precise estimation static sites, disease-free survival (DFS) between primary of outcome may benefit breast cancer patients in clinical breast cancer diagnosis and metastatic recurrence, first- practice, thus achieving long-term survival. However, the line therapy and overall survival (OS) from the onset clinicopathological characteristics and the risk factors of metastasis to death were retrospectively collected. that affect the incidence and prognosis of BCLM remain DFS was divided as ≤2 years, > 2 years and patients with poorly identified in the Han population. de-novo diseases were classified as M1 group. Cancers In this article, we summarized the clinicopathological with 1–100% estrogen receptor or progesterone recep- features and explored the risk factors associated with the tor routine immunohistochemistry (IHC) staining were morbidity and mortality of BCLM in newly diagnosed considered hormone receptor-positive (HR+). Human MBC patients in China, which may help identify cases epidermal growth factor receptor 2 (HER2) overexpres- with higher odds of lung metastases and worse survival. sion was defined as IHC3+ or in the case of IHC2+, fluo- Early intervention and multidisciplinary treatment for rescent in-situ hybridization (FISH) positive. The HER2 BCLM patients are of utmost importance. status was determined according to the American Soci- ety of Clinical Oncology (ASCO)/College of American Methods Pathologists (CAP) guidelines. Since the ASCO/CAP This work was approved by the institutional review board guidelines have updated across years, the HER2 status of National Cancer Center/National Clinical Research was evaluated based on different versions in certain years Center for Cancer/Cancer Hospital, Chinese Academy (2000–2019). The receptor status of metastatic tumors of Medical Sciences and Peking Union Medical College. was re-assessed in 512/2263 (22.7%) cases. Breast cancer All methods were carried out in accordance with relevant subtypes were divided as HR+/HER2-, HR−/HER2+, guidelines and regulations. The study methods referred HR+/HER2+ and triple-negative (HR−/HER2-), based to the previous report [11]. on primary tumor. Tumor staging of the primary tumor was based on the 8th American Joint Committee on Can- Study population cer (AJCC) TNM staging system. We attained clinical data of 3155 MBC patients initially diagnosed between April 2000 and September 2019 from Statistical analysis the China National Cancer Center database. The database Chi-square or Fisher’s exact test were used for category was generated and maintained by medical staff, drawn variables to compare the clinicopathological features from the medical records in the hospital information among different subtypes in patients with lung metas- system of China National Cancer Center. Several studies tases. Incidence of lung metastases was defined as the based on this database have been published [11–13]. We number of BCLM patients divided by the total number removed patients with unknown tumor receptor status of MBC patients. We performed multivariate logistic (n = 579), unknown distant metastases (n = 65) and fol- regression to explore factors associated with the presence low-up no more than 1 month since the initial diagnosis of lung metastases upon initial diagnosis of MBC. We cal- of MBC (n = 254) from this cohort, finally leaving 2263 culated odds ratios (ORs) and 95% confidence intervals patients for incidence analysis. Among these, 809 cases (CIs) in the model. Kaplan-Meier method was utilized presented with lung metastases (including lymphangitic to estimate the survival within subsets and log-rank test carcinomatosis and pleural disease) upon initial MBC was used to analyze the differences. We conducted uni- diagnosis. Lung metastases were identified by enhanced variate and multivariate Cox regression analyses to inves- chest CT scan and 220/809 (27.2%) patients were biopsy tigate the independent predictive factors significantly
Lin et al. BMC Cancer (2021) 21:1330 Page 3 of 9 Table 1 Clinicopathological characteristics of patients with lung metastases upon initial metastatic breast cancer diagnosis according to breast cancer subtype Characteristic HR+/HER2-, N (%) HR−/HER2+, N (%) HR+/HER2+, N (%) Triple-negative, p value N (%) All patients 386 (47.7) 116 (14.3) 130 (16.1) 177 (21.9) Age 0.015
Lin et al. BMC Cancer (2021) 21:1330 Page 4 of 9 associated with the prognosis of BCLM patients. All the Table 3 Multivariate logistic regression for the presence of lung statistics were analyzed using SPSS statistical software metastases at initial diagnosis of metastatic breast cancer version 23.0 package. A two-sided p value of 0.05 or less Characteristic OR (95% CI) p value was significantly different. Age
Lin et al. BMC Cancer (2021) 21:1330 Page 5 of 9 (vs.
Lin et al. BMC Cancer (2021) 21:1330 Page 6 of 9 Fig. 2 Overall survival of BCLM patients according to breast cancer subtype. BCLM, breast cancer lung metastases, HR, hormone receptor, HER2, human epidermal growth factor receptor 2, TNBC, triple-negative 35.7% of all MBC patients. Compared with other groups, that the knockdown of hnRNPM might reduce lung patients with triple-negative subtype had the highest metastatic potential of TNBC cells with mutant MORC2 percentage of lung metastases, consistent with previ- [20]. Another research revealed that the overexpression ous findings [14–16]. The incidence of lung metastasis of transcription and export complex 2 subunit (ENY2) in triple-negative breast cancer (TNBC) could reach up could promote TNBC progression and lung metastasis to 40% [17], similar with 42.3% in our data. Addition- both in vitro and in vivo [21]. Further mechanisms clari- ally, the prognosis of BCLM patients differed remark- fying TNBC lung metastasis are certainly worth explor- ably in tumor subtypes, varying between 26.8 months ing, which may provide potential targets for new drugs. of triple-negative subtype and 49.0 months of HR+/ Our data also indicated that patients with older age HER2- subtype. and worse performance status were more likely to pre- Our study confirmed the results that TNBC was more sent with lung metastases at initial MBC diagnosis. aggressive and preferred to develop lung metastases. The The increasing risk of lung metastases associated with molecular mechanisms underlying TNBC metastasis to aging was consistently found in population-based stud- lung might offer therapeutic targets for clinical preven- ies [6, 22]. On the contrary, previous studies observed tion and management. Minn et al. [18] identified fascin that younger patients had a higher risk of liver metas- as a mediator promoting basal-like breast cancer metas- tases [5, 23]. Increased levels of urinary prostaglandin tasis to lung, due to its close association with cell motility. E-metabolite (PGE-M), a biomarker of inflammation, Iriondo et al. [19] observed that inhibition of transform- were observed in aging and lung metastases in patients ing growth factor-β1-activated kinase-1 (TAK1) could with breast cancer [24]. Levels of multiple proinflam- suppress lung metastasis in TNBC, which might provide matory mediators, known as inducers of cyclooxyge- a novel target for impairing TNBC lung metastasis. A nase-2 (COX-2) and prostaglandin E2 (PGE2) synthesis, single mutation on microrchidia family CW-type zinc elevated during aging, which contributed to the finger 2 (MORC2) promoted TNBC lung metastasis by increase of PGE-M, a catabolic product of P GE2 [25]. regulating heterogeneous nuclear ribonucleoprotein M Overexpression of COX-2 in tumor cells within the (hnRNPM)- mediated CD44 splicing, which indicated lung metastases could explain the increased level of
Lin et al. BMC Cancer (2021) 21:1330 Page 7 of 9 Table 4 Univariate and multivariate cox regression analyses of OS in BCLM patients Univariable analysis Multivariable analysis Characteristic Hazard ratio (95% CI) p value Characteristic Hazard ratio (95% CI) p value Age Age
Lin et al. BMC Cancer (2021) 21:1330 Page 8 of 9 PGE-M [26]. It’s possible that age-related inflammatory important risk factor for BCLM patients [36], but it was conditions mediated breast cancer metastasis to the not documented in detail in our database. Finally, the lung. The predictive features associated with different retrospective nature of this research and relatively small metastatic sites may help clinicians distinguish patients population require future studies to confirm the results. with distinct organ-specific metastases during the clini- cal practice. Conclusions The BCLM patients in our data achieved a median Our study provides essential information on clinico- OS of 41.7 months since MBC diagnosis, among which pathological features and survival outcomes of BCLM triple-negative subtype experienced the worst out- patients at initial diagnosis of MBC in China. The risk come of 26.8 months and HR+/HER2- subtype the best factors identified here help to screen breast cancer of 49.0 months. The prognosis of MBC patients var- patients with high odds of lung metastases and BCLM ied remarkably by the metastatic organs, with the best patients with high risk of mortality. The early detection of for bone, followed by lung, liver and the worst for brain metastases and proper evaluation of prognosis in clinical metastases [7, 27]. Previous findings recorded a survival practice are beneficial to optimize the disease outcomes. ranging from 21.0 to 58.5 months in MBC patients with lung metastases [1, 6, 28]. A pulmonary metastasec- tomy study reported a median survival of 23.6 months Abbreviations in TNBC patients with an isolated and limited num- MBC: Metastatic breast cancer; BCLM: Breast cancer lung metastases; ECOG: East- ern Cooperative Oncology Group; DFS: Disease-free survival; OS: Overall survival; ber of lung metastases, significantly poorer than HR+ IHC: Immunohistochemistry; HR: Hormone receptor; HER2: Human epidermal or HER2+ patients [29]. A population-based research growth factor receptor 2; FISH: Fluorescent in-situ hybridization; ASCO/CAP: Ameri- showed that TNBC patients with metastases confined to can Society of Clinical Oncology/College of American Pathologists; AJCC: Ameri- can Joint Committee on Cancer; ILC: Invasive lobular carcinoma; IDC: Invasive lung had a median OS of only 14.0 months [30]. TNBC is ductal carcinoma; OR: Odds ratio; CI: Confidence interval; TNBC: Triple-negative still lethal and remains intractable to existing treatments, breast cancer; TAK1: Transforming growth factor-β1-activated kinase-1; MORC2: extremely desirable for novel therapies to improve the Microrchidia family CW-type zinc finger 2; hnRNPM: Heterogeneous nuclear ribonucleoprotein M; ENY2: Transcription and export complex 2 subunit; PGE-M: prognosis. Prostaglandin E-metabolite; COX-2: Cyclooxygenase-2; PGE2: Prostaglandin E2. We also identified prognostic factors for survival of BCLM patients and found that worse performance sta- Acknowledgements Not applicable. tus, triple-negative subtype, the simultaneous presence of liver metastases, multi-metastatic sites and shorter DFS Authors’ contributions were significantly correlated with poor outcome. Multi- BX directed the study and was responsible for study design. SL performed the statistical analysis and drafted the initial manuscript. All authors collected clini- ple sites of first metastases had significantly unfavorable cal data. All authors read and approved the final manuscript. prognosis than single site first metastases [31, 32]. In our data, the extrapulmonary metastases had 1.7 times of Funding This study was supported by grants from National Key R&D Program of China mortality risk than lung-only metastases at MBC diagno- (2018YFC1312101) and Chinese Academic of Medical Sciences Initiative for sis. Brain metastases also worsen the outcome of BCLM Innovative Medicine (CAMS-12 M-1-010). patients but the difference did not reach significance, Availability of data and materials probably due to the late onset of brain metastases dur- The data used during the current study are available from the corresponding ing the clinical course, with an incidence of only 6.90 to author on reasonable request. 7.56% in newly MBC diagnosis patients [32–34]. BCLM patients with DFS shorter than 2 years experienced Declarations poorer survival, which indicated the intrinsic aggressive- Ethics approval and consent to participate ness of the tumors. All methods were carried out in accordance with relevant guidelines and There were some limitations in our study. Firstly, dis- regulations. This work was approved by the institutional review board of cordance in tumor phenotype has been reported in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical multiple studies [35], but we did not have enough infor- College. mation on the receptor status of metastatic tumors, which might cause some bias in the analysis of incidence Consent for publication The informed consent was obtained from all participants. and survival outcomes when stratified by breast cancer subtype. Secondly, the fact that less than half of BCLM Competing interests patients with HER2-positive received anti-HER2 therapy The authors declare that they have no competing interests. during first line limits the generalizability of the outcome Received: 9 July 2021 Accepted: 17 November 2021 results. Additionally, the number of lung lesions was an
Lin et al. BMC Cancer (2021) 21:1330 Page 9 of 9 References 20. Zhang FL, Cao JL, Xie HY, Sun R, Yang LF, Shao ZM, et al. Cancer-associated 1. Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The Clinicopathological features MORC2-mutant M276I regulates an hnRNPM-mediated CD44 splicing and survival outcomes of patients with different metastatic sites in stage IV switch to promote invasion and metastasis in triple-negative breast Cancer. breast cancer. BMC Cancer. 2019;19:1091. Cancer Res. 2018;78:5780–92. 2. Largillier R, Ferrero JM, Doyen J, Barriere J, Namer M, Mari V, et al. Prog- 21. Xie G, Yang H, Ma D, Sun Y, Chen H, Hu X, et al. Integration of whole- nostic factors in 1,038 women with metastatic breast cancer. Ann Oncol. genome sequencing and functional screening identifies a prognostic 2008;19:2012–9. signature for lung metastasis in triple-negative breast cancer. Int J Cancer. 3. Friedel G, Pastorino U, Ginsberg RJ, Goldstraw P, Johnston M, Pass H, et al. 2019;145:2850–60. Results of lung metastasectomy from breast cancer: prognostic criteria on 22. Chen MT, Sun HF, Zhao Y, Fu WY, Yang LP, Gao SP, et al. Comparison of pat- the basis of 467 cases of the international registry of lung metastases. Eur J terns and prognosis among distant metastatic breast cancer patients by Cardiothorac Surg. 2002;22:335–44. age groups: a SEER population-based analysis. Sci Rep. 2017;7:9254. 4. Diaz-Canton EA, Valero V, Rahman Z, Rodriguez-Monge E, Frye D, Smith T, 23. Xie J, Xu Z. A population-based study on liver metastases in women et al. Clinical course of breast cancer patients with metastases confined with newly diagnosed breast Cancer. Cancer Epidemiol Biomark Prev. to the lungs treated with chemotherapy. The University of Texas M.D. 2019;28:283–92. Anderson Cancer center experience and review of the literature. Ann Oncol. 24. Morris PG, Zhou XK, Milne GL, Goldstein D, Hawks LC, Dang CT, et al. 1998;9:413–8. Increased levels of urinary PGE-M, a biomarker of inflammation, occur in 5. Cummings MC, Simpson PT, Reid LE, Jayanthan J, Skerman J, Song S, et al. association with obesity, aging, and lung metastases in patients with breast Metastatic progression of breast cancer: insights from 50 years of autopsies. cancer. Cancer Prev Res (Phila). 2013;6:428–36. J Pathol. 2014;232:23–31. 25. Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory 6. Xiao W, Zheng S, Liu P, Zou Y, Xie X, Yu P, et al. Risk factors and survival cytokines. Curr Opin Hematol. 2001;8:131–6. outcomes in patients with breast cancer and lung metastasis: a population- 26. Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. based study. Cancer Med. 2018;7:922–30. 2010;10:181–93. 7. Ording AG, Heide-Jørgensen U, Christiansen CF, Nørgaard M, Acquavella J, 27. Kast K, Link T, Friedrich K, Petzold A, Niedostatek A, Schoffer O, et al. Impact Sørensen HT. Site of metastasis and breast cancer mortality: a Danish nation- of breast cancer subtypes and patterns of metastasis on outcome. Breast wide registry-based cohort study. Clin Exp Metastasis. 2017;34:93–101. Cancer Res Treat. 2015;150:621–9. 8. Medeiros B, Allan AL. Molecular mechanisms of breast Cancer metas- 28. Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G, et al. tasis to the lung: clinical and experimental perspectives. Int J Mol Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Sci. 2019;20(9):2272. Metastasis. 2015;32:125–33. 9. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th 29. Yhim HY, Han SW, Oh DY, Han W, Im SA, Kim TY, et al. Prognostic factors ESO-ESMO international consensus guidelines for advanced breast Cancer for recurrent breast cancer patients with an isolated, limited number of (ABC 4)†. Ann Oncol. 2018;29:1634–57. lung metastases and implications for pulmonary metastasectomy. Cancer. 10. Handy JR, Bremner RM, Crocenzi TS, Detterbeck FC, Fernando HC, Fidias 2010;116:2890–901. PM, et al. Expert consensus document on pulmonary Metastasectomy. Ann 30. Zhao HY, Gong Y, Ye FG, Ling H, Hu X. Incidence and prognostic factors of Thorac Surg. 2019;107:631–49. patients with synchronous liver metastases upon initial diagnosis of breast 11. Lin S, Mo H, Li Y, Guan X, Chen Y, Wang Z, et al. Risk factors and survival of cancer: a population-based study. Cancer Manag Res. 2018;10:5937–50. patients with liver metastases at initial metastatic breast Cancer diagnosis in 31. Van Mechelen M, Van Herck A, Punie K, Nevelsteen I, Smeets A, Neven P, Han population. Front Oncol. 2021;11:670723. et al. Behavior of metastatic breast cancer according to subtype. Breast 12. Li Y, Li Q, Mo H, Guan X, Lin S, Wang Z, et al. Incidence, risk factors and Cancer Res Treat. 2020;181:115–25. survival of patients with brain metastases at initial metastatic breast cancer 32. Leone BA, Vallejo CT, Romero AO, Machiavelli MR, Pérez JE, Leone J, et al. diagnosis in China. Breast. 2021;55:30–6. Prognostic impact of metastatic pattern in stage IV breast cancer at initial 13. Lin S, Mo H, Li Y, Guan X, Chen Y, Wang Z, et al. Development and validation diagnosis. Breast Cancer Res Treat. 2017;161:537–48. of a nomogram for predicting survival of advanced breast cancer patients in 33. Martin AM, Cagney DN, Catalano PJ, Warren LE, Bellon JR, Punglia RS, et al. China. Breast. 2020;53:172–80. Brain metastases in newly diagnosed breast Cancer: a population-based 14. Rodríguez-Pinilla SM, Sarrió D, Honrado E, Hardisson D, Calero F, Ben- study. JAMA Oncol. 2017;3:1069–77. itez J, et al. Prognostic significance of basal-like phenotype and fascin 34. Zhao W, Wu L, Zhao A, Zhang M, Tian Q, Shen Y, et al. A nomogram for expression in node-negative invasive breast carcinomas. Clin Cancer Res. predicting survival in patients with de novo metastatic breast cancer: a 2006;12:1533–9. population-based study. BMC Cancer. 2020;20:982. 15. Soni A, Ren Z, Hameed O, Chanda D, Morgan CJ, Siegal GP, et al. Breast 35. Schrijver W, Suijkerbuijk KPM, van Gils CH, van der Wall E, Moelans CB, van cancer subtypes predispose the site of distant metastases. Am J Clin Pathol. Diest PJ. Receptor conversion in distant breast Cancer metastases: a system- 2015;143:471–8. atic review and Meta-analysis. J Natl Cancer Inst. 2018;110:568–80. 16. Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X. Breast cancer lung metas- 36. Chen F, Fujinaga T, Sato K, Sonobe M, Shoji T, Sakai H, et al. Clinical features tasis: molecular biology and therapeutic implications. Cancer Biol Ther. of surgical resection for pulmonary metastasis from breast cancer. Eur J Surg 2018;19:858–68. Oncol. 2009;35:393–7. 17. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48. 18. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that medi- Publisher’s Note ate breast cancer metastasis to lung. Nature. 2005;436:518–24. Springer Nature remains neutral with regard to jurisdictional claims in pub- 19. Iriondo O, Liu Y, Lee G, Elhodaky M, Jimenez C, Li L, et al. TAK1 mediates lished maps and institutional affiliations. microenvironment-triggered autocrine signals and promotes triple-nega- tive breast cancer lung metastasis. Nat Commun. 2018;9:1994.