Table Info

Table 1.

Summary of ongoing clinical trials and observational studies in breast cancer treatment in relation to gut microbiota

Study	Aims	Study type	Sample size
“Engineering gut microbiome to target breast cancer” [42]	To determine whether probiotics will help the body’s immune system react to breast cancer	Clinical trial	7
“Gut microbiome and GI toxicities as determinants of response to neoadjuvant chemo for advanced breast cancer” [41]	To determine whether gut microbial composition can influence immune response to the tumour, resulting in inter-individual differences in the response to anti-cancer therapies	Clinical trial	40
“Intestinal microbiota of breast cancer patients undergoing chemotherapy” [43]	To study specific types (or groups) of bacteria that promote the occurrence, development, and mechanism of breast cancer	Observational	80
“Breast cancer and its relationship with the microbiota” [44]	To examine associated between composition and functionality of the mammary/gut microbiota with breast cancer risk, and to determine if exposure to environmental contaminants [endocrine disruptors, endocrine disrupting chemicals (EDCs)] can alter the microbiota?	Observational	200
“Determinants of acquired endocrine resistance in metastaticbreast cancer: a pilot study” [45]	To identify markers of endocrine resistance in ctDNA and the gut microbiome in patients with estrogen (Oestrogen) receptor positive (ER⁺) HER2^– metastatic breast cancer	Observational	20
“Study to investigate efficacy of a novel probiotic on the bacteriome and mycobiome of breast cancer” [46]	To examine the effect of probiotics on the breast tumour microbiome and gut microbiome in breast cancer	Clinical trial	100
“Effects of chemotherapy on intestinal bacteria in patients with newly diagnosed breast cancer” [47]	To study effects of chemotherapy on intestinal bacteria/organisms in patients newly diagnosed with breast cancer	Observational	36
“ARGONAUT: stool and blood sample bank for cancer patients” [40]	To determine whether the microbiota composition can predict progression-free survival. Whole genome sequencing and metabolomics will be used to characterize the patient’s microbiome, and whether there is any correlation with response to treatment	Observational	4,000
“Gut and intratumoural microbiome effect on the neoadjuvant chemotherapy-induced immunosurveillance in triple negative breast cancer” [48]	To determine if the probability of pathologic complete response in triple negative breast cancer patients treated with standard of care neoadjuvant chemotherapy is correlated with variability in the composition of intestinal and intra-tumoral microbiota and subsequent short-term alterations in composition	Observational	49
“The clinical study of modern therapies on flora in body fluids and blood of malignant tumour patients” [49]	To study what modern therapies lead to the influence of microecological environment including diversity and abundance of bacteria in patients who received malignant tumours	Observational	500

Declarations

Acknowledgements

With thanks to Pat Bain, Graphic Designer, Media Services, Rowett Institute, University of Aberdeen.

Author contributions

EB, SM, GU and BE contributed to conception and design of the review. EB and SM wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. First authorship is shared between SM and EB as both authors equally contributed and worked on the manuscript.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Cancerresearchuk.org [Internet]. London: Cancer Research UK; c2020 [cited 2020 Mar]. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer

Lacey JV Jr, Kreimer AR, Buys SS, Marcus PM, Chang SC, Leitzmann MF, et al. Breast cancer epidemiology according to recognized breast cancer risk factors in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial Cohort. BMC Cancer. 2009;9:84. [DOI] [PubMed] [PMC]

Selber-Hnatiw S, Rukundo B, Ahmadi M, Akoubi H, Al-Bizri H, Aliu AF, et al. Human gut microbiota: toward an ecology of disease. Front Microbiol. 2017;8:1265. [DOI] [PubMed] [PMC]

Fernández MF, Reina-Pérez I, Astorga JM, Rodríguez-Carrillo A, Plaza-Díaz J, Fontana L. Breast cancer and its relationship with the microbiota. Int J Environ Res Public Health. 2018;15:1747. [DOI]

Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800–12. [DOI] [PubMed] [PMC]

Goedert JJ, Jones G, Hua X, Xu X, Yu G, Flores R, et al. Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study. J Natl Cancer Inst. 2015;107:djv147. [DOI] [PubMed] [PMC]

Luu TH, Michel C, Bard JM, Dravet F, Nazih H, Bobin-Dubigeon C. Intestinal proportion of Blautia sp. is associated with clinical stage and histoprognostic grade in patients with early-stage breast cancer. Nutr Cancer. 2017;69:267–75. [DOI] [PubMed]

Wen L, Duffy A. Factors influencing the gut microbiota, inflammation, and type 2 diabetes. J Nutr. 2017;147:1468S–75S. [DOI] [PubMed] [PMC]

David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2013;505:559–63. [DOI] [PubMed] [PMC]

10.

Saad R, Rizkallah MR, Aziz RK. Gut pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012;4:16. [DOI] [PubMed] [PMC]

11.

Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol. 2017;14:356–65. [DOI] [PubMed]

12.

Samet A, Sledzińska A, Krawczyk B, Hellmann A, Nowicki A, Kur J, et al. Leukemia and risk of recurrent Escherichia coli bacteremia: genotyping implicates E. coli translocation from the colon to the bloodstream. Eur J Clin Microbiol Infect Dis. 2013;32:1393–400. [DOI] [PubMed] [PMC]

13.

Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342:971–6. [DOI] [PubMed] [PMC]

14.

Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342:967–70. [DOI] [PubMed] [PMC]

15.

Paci A, Veal G, Bardin C, Levêque D, Widmer N, Beijnen J, et al. Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer. 2014;50:2010–9. [DOI] [PubMed]

16.

Montassier E, Batard E, Massart S, Gastinne T, Carton T, Caillon J, et al. 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation. Microb Ecol. 2014;67:690–9. [DOI] [PubMed]

17.

Faber J, van Limpt K, Diane Kegler, Luiking Y, Garssen J, van Helvoort A, et al. Bacterial translocation is reduced by a specific nutritional combination in mice with chemotherapy-induced neutropenia. J Nutr. 2011;141:1292–8. [DOI] [PubMed]

18.

Li XL, Wang CZ, Mehendale SR, Sun S, Wang Q, Yuan CS, et al. Panaxadiol, a purified ginseng component, enhances the anti-cancer effects of 5-fluorouracil in human colorectal cancer cells. Cancer Chemother Pharmacol. 2009;64:1097–104. [DOI] [PubMed]

19.

Tang Q, Zuo T, Lu S, Wu J, Wang J, Zheng R, et al. Dietary squid ink polysaccharides ameliorated the intestinal microflora dysfunction in mice undergoing chemotherapy. Food Funct. 2014;5:2529–35. [DOI] [PubMed]

20.

Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014;25:1919–29. [DOI] [PubMed]

21.

Taper HS, Roberfroid MB. Nontoxic potentiation of cancer chemotherapy by dietary oligofructose or inulin. Nutr Cancer. 2000;38:1–5. [DOI] [PubMed]

22.

Di Modica M, Regondi V, Gargari G, Bonizzi A, Arioli S, Belmonte B, et al. Abstract 4959: the gut microbiota contributes to the effectiveness of HER2-targeted therapy. Immunology. 2019;79:4959. [DOI]

23.

Tagliabue E, Modica M, Gargari G, Regondi V, Bonizzi A, Arioli S, et al. Abstract P4-10-32: commensal gut microbiota influences efficacy of trastuzumab in patients with HER2-positive breast carcinoma. Cancer Res. 2020;80:4-10–32. [DOI]

24.

Parida S, Sharma D. The microbiome-estrogen connection and breast cancer risk. Cells. 2019;8:1642. [DOI]

25.

Plottel CS, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. 2011;10:324–35. [DOI] [PubMed] [PMC]

26.

Kwa M, Plottel CS, Blaser MJ, Adams S. The intestinal microbiome and estrogenreceptor-positive female breast cancer. J Natl Cancer Inst. 2016;108:djw029. [DOI]

27.

Goldin BR, Adlercreutz H, Gorbach SL, Warram JH, Dwyer JT, Swenson L, et al. Estrogen excretion patterns and plasma levels in vegetarian and omnivorous women. N Engl J Med. 1982;307:1542–7. [DOI] [PubMed]

28.

Chen KLA, Liu X, Zhao YC, Hieronymi K, Rossi G, Auvil LS, et al. Long-term administration of conjugated estrogen and bazedoxifene decreased murine fecal β-glucuronidase activity without impacting overall microbiome community. Sci Rep. 2018;8:8166. [DOI] [PubMed] [PMC]

29.

Helland T, Henne N, Bifulco E, Naume B, Borgen E, Kristensen VN, et al. Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients. Breast Cancer Res. 2017;19:125. [DOI] [PubMed] [PMC]

30.

Voutsadakis IA. Immune blockade inhibition in breast cancer. Anticancer Res. 2016;36:5607–22. [DOI] [PubMed]

31.

Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament F, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–84. [DOI] [PubMed] [PMC]

32.

Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer. 2017;17:271–85. [DOI] [PubMed]

33.

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7. [DOI] [PubMed]

34.

Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8. [DOI] [PubMed] [PMC]

35.

Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–9. [DOI] [PubMed] [PMC]

36.

Buchta Rosean C, Bostic RR, Ferey JCM, Feng TY, Azar FN, Tung KS, et al. Preexisting commensal dysbiosis is a host-intrinsic regulator of tissue inflammation and tumor cell dissemination in hormone receptor-positive breast cancer. Cancer Res. 2019;79:3662–75. [DOI] [PubMed] [PMC]

37.

Allegrezza MJ, Rutkowski MR, Stephen TL, Svoronos N, Perales-Puchalt A, Nguyen JM, et al. Trametinib drives T-cell-dependent control of KRAS-mutated tumors by inhibiting pathological myelopoiesis. Cancer Res. 2016;76:6253–65. [DOI] [PubMed] [PMC]

38.

Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med. 2013;210:2435–66. [DOI] [PubMed] [PMC]

39.

Yamashita H, Ogiya A, Shien T, Horimoto Y, Masuda N, Inao T, et al. Clinicopathological factors predicting early and late distant recurrence in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer. 2016;23:830–43. [DOI] [PubMed]

40.

Persephone Biosciences. ARGONAUT: Stool and blood sample bank for cancer patients [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2020 [updated 2021 Feb 23; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04638751?term=gut+microbiome&cond=Breast+Cancer&draw=3&rank=13

41.

University of Arkansas. Gut microbiome & gastrointestinal toxicities as determinants of response to neoadjuvant chemofor advanced breast cancer [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2016 [updated 2021 Jun 15; cited 2020 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02696759?term=gut+microbiome&cond=Breast+Cancer&draw=4&rank=3

42.

Mayo Clinic. Engineering gut microbiome to target breast cancer [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2017 [updated 2021 May 21; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03358511?term=gut+microbiome&cond=Breast+Cancer&draw=2

43.

First Affiliated Hospital of Harbin Medical University. Intestinal microbiota of breast cancer patients undergoing chemotherapy [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2019 [updated 2019 Oct 25; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04138979?term=gut+microbiome&cond=Breast+Cancer&draw=2&rank=4

44.

Universidad de Granada. Breast cancer and its relationship with the microbiota [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2019 [updated 2021 May 13; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03885648?term=gut+microbiome&cond=Breast+Cancer&draw=2&rank=5

45.

Sunnybrook Health Sciences Centre. Determinants of acquired endocrine resistance in metastatic breast cancer: a pilot study [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2020 [updated 2021 Oct 19; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04579484?term=gut+microbiome&cond=Breast+Cancer&draw=2&rank=6

46.

Case Comprehensive Cancer Center. Study to investigate efficacy of a novel probiotic on the bacteriome and mycobiome of breast cancer [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2020 [updated 2021 May 7; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04362826?term=gut+microbiome&cond=Breast+Cancer&draw=2&rank=9

47.

University of Southern California. Effects of chemotherapy on intestinal bacteria in patients with newly diagnosed breast cancer [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2015 [updated 2019 Jun 18; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02370277?term=gut+microbiome&cond=Breast+Cancer&draw=2&rank=10

48.

Hackensack Meridian Health. Gut and intratumoral microbiome effect on the neoadjuvant chemotherapy-induced immunosurveillance in triple negative breast cancer [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2018 [updated 2021 Jul 2; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03586297?term=gut+microbiome&cond=Breast+Cancer&draw=3&rank=16

49.

The First Affiliated Hospital of Dalian Medical University. The clinical study of modern therapies on flora in body fluids and blood of malignant tumor patients [Internet]. ClinicalTrials.gov: National Library of Medicine (US); c2018 [updated 2019 Dec 18; cited 2021 Apr 9]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04202848?term=gut+microbiome&cond=Breast+Cancer&draw=4&rank=27.

50.

Fletcher O, Dudbridge F. Candidate gene-environment interactions in breast cancer. BMC Med. 2014;12:195. [DOI] [PubMed] [PMC]

51.

Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell. 2014;159:789–99. [DOI] [PubMed] [PMC]

52.

Lim YW, Chen-Harris H, Mayba O, Lianoglou S, Wuster A, Bhangale T, et al. Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration. Proc Natl Acad Sci USA. 2018;115:E11701–10. [DOI] [PubMed] [PMC]

53.

Ogino S, Nowak JA, Hamada T, Milner DA Jr, Nishihara R. Insights into pathogenic interactions among environment, host, and tumor at the crossroads of molecular pathology and epidemiology. Annu Rev Pathol. 2019;14:83–103. [DOI] [PubMed] [PMC]

54.

Ogino S, Nishihara R, Vander Weele TJ, Wang M, Nishi A, Lochhead P, et al. Review article: the role of molecular pathological epidemiology in the study of neoplastic and non-neoplastic diseases in the era of precision medicine. Epidemiology. 2016;27:602–11. [DOI] [PubMed] [PMC]