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New insights into breast microcalcification for poor prognosis: NACT cohort and bone metastasis evaluation cohort

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Abstract

Objectives

The study aimed to analyze the poor prognosis of microcalcification in breast cancer (BC), including the pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and the risk of bone metastases.

Materials and methods

313 breast cancer patients received NACT to evaluate pCR and 1182 patients from a multicenter database to assess bone metastases were retrospectively included. Two groups were divided according to the presence or absence of mammography microcalcification. Clinical data, image characteristics, neoadjuvant treatment response, bone involvement, and follow-up information were recorded. The pCR and bone metastases were compared between subgroups using the Mann–Whitney and χ2 tests and logistic regression, respectively.

Results

Mammographic microcalcification was associated with a lower pCR than uncalcified BC in the NACT cohort (20.6% vs 31.6%, P = 0.029). Univariate and multivariate analysis suggested that calcification was a risk factor for poor NACT response [OR = 1.780, 95%CI (1.065–2.974), P = 0.028], [OR = 2.352, 95%CI (1.186–4.667), P = 0.014]. Microcalcification was more likely to be necrosis on MRI than those without microcalcification (53.0% vs 31.7%, P < 0.001), multivariate analysis indicated that tumor necrosis was also a risk factor for poor NACT response [OR = 2.325, 95%CI (1.100–4.911), P = 0.027]. Age, menopausal status, breast density, mass, molecular, and pathology type were not significantly associated with non-pCR risk assessment. In a multicenter cohort of 1182 patients with pathologically confirmed BC, those with microcalcifications had a higher proportion of bone metastases compared to non-calcified BC (11.6% vs 4.9%, P < 0.001). Univariate and multivariate analysis showed that microcalcification was an independent risk factor for bone metastasis [OR = 2.550, 95%CI (1.620–4.012), P < 0.001], [OR = 2.268(1.263–4.071), P = 0.006)]. Osteolytic bone metastases predominated but there was no statistical difference between the two groups (78.9% vs 60.7%, P = 0.099). Calcified BC was mainly involved in axial bone, but was more likely to involve the whole-body bone than non-calcified BC (33.8% vs 10.7%, P = 0.021).

Conclusion

This study provides important insights into the poor prognosis of microcalcification, not only in terms of poor response to NACT but also the risk factor of bone metastases.

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Data availability

This paper involved data from the internal studies of our institutions, which are not publicly available to protect patient privacy. Further inquiries can be directed to the corresponding author.

References

  • Azam S, Eriksson M, Sjölander A, Gabrielson M, Hellgren R, Czene K et al (2021) Mammographic microcalcifications and risk of breast cancer. Br J Cancer 125(5):759–765

    PubMed  PubMed Central  Google Scholar 

  • Bado IL, Zhang W, Hu J, Xu Z, Wang H, Sarkar P et al (2021) The bone microenvironment increases phenotypic plasticity of ER(+) breast cancer cells. Dev Cell 56(8):1100-1117 e1109

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chiou AE, Liu C, Moreno-Jiménez I, Tang T, Wagermaier W, Dean MN et al (2021) Breast cancer-secreted factors perturb murine bone growth in regions prone to metastasis. Sci Adv. https://doi.org/10.1126/sciadv.abf2283

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi S, Friedrichs J, Song YH, Werner C, Estroff LA, Fischbach C (2019) Intrafibrillar, bone-mimetic collagen mineralization regulates breast cancer cell adhesion and migration. Biomaterials 198:95–106

    CAS  PubMed  Google Scholar 

  • Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N et al (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172

    PubMed  Google Scholar 

  • Cox RF, Hernandez-Santana A, Ramdass S, McMahon G, Harmey JH, Morgan MP (2012) Microcalcifications in breast cancer: novel insights into the molecular mechanism and functional consequence of mammary mineralisation. Br J Cancer 106(3):525–537

    CAS  PubMed  PubMed Central  Google Scholar 

  • Feliciano Y, Mamtani A, Morrow M, Stempel MM, Patil S, Jochelson MS (2017) Do calcifications seen on mammography after neoadjuvant chemotherapy for breast cancer always need to be excised? Ann Surg Oncol 24(6):1492–1498

    PubMed  Google Scholar 

  • Goldberg H, Zandbank J, Kent V, Leonov-Polak M, Livoff A, Chernihovsky A et al (2017) Chemotherapy may eradicate ductal carcinoma in situ (DCIS) but not the associated microcalcifications. Eur J Surg Oncol 43(8):1415–1420

    CAS  PubMed  Google Scholar 

  • Goorts B, Dreuning KMA, Houwers JB, Kooreman LFS, Boerma EG, Mann RM et al (2018) MRI-based response patterns during neoadjuvant chemotherapy can predict pathological (complete) response in patients with breast cancer. Breast Cancer Res 20(1):34

    PubMed  PubMed Central  Google Scholar 

  • Haider MT, Smit DJ, Taipaleenmäki H (2020) The endosteal niche in breast cancer bone metastasis. Front Oncol 10:335

    PubMed  PubMed Central  Google Scholar 

  • Haider MT, Ridlmaier N, Smit DJ, Taipaleenmäki H (2021) Interleukins as mediators of the tumor cell-bone cell crosstalk during the initiation of breast cancer bone metastasis. Int J Mol Sci 22(6):2898

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hartkopf AD, Taran FA, Wallwiener M, Hagenbeck C, Melcher C, Krawczyk N et al (2013) The presence and prognostic impact of apoptotic and nonapoptotic disseminated tumor cells in the bone marrow of primary breast cancer patients after neoadjuvant chemotherapy. Breast Cancer Res 15(5):R94

    PubMed  PubMed Central  Google Scholar 

  • Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C et al (1996) Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335(24):1785–1791

    CAS  PubMed  Google Scholar 

  • Hu Y, Xu W, Zeng H, He Z, Lu X, Zuo D et al (2020) OXPHOS-dependent metabolic reprogramming prompts metastatic potential of breast cancer cells under osteogenic differentiation. Br J Cancer 123(11):1644–1655

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Cao J, Zhou Y, Mao F, Shen S, Sun Q (2019) Mammographic casting-type calcification is an independent prognostic factor in invasive breast cancer. Sci Rep 9(1):10544

    PubMed  PubMed Central  Google Scholar 

  • Månsson E, Bergkvist L, Christenson G, Persson C, Wärnberg F (2009) Mammographic casting-type calcifications is not a prognostic factor in unifocal small invasive breast cancer: a population-based retrospective cohort study. J Surg Oncol 100(8):670–674

    PubMed  Google Scholar 

  • Marinovich ML, Sardanelli F, Ciatto S, Mamounas E, Brennan M, Macaskill P et al (2012) Early prediction of pathologic response to neoadjuvant therapy in breast cancer: systematic review of the accuracy of MRI. Breast 21(5):669–677

    CAS  PubMed  Google Scholar 

  • Marinovich ML, Houssami N, Macaskill P, Sardanelli F, Irwig L, Mamounas EP et al (2013) Meta-analysis of magnetic resonance imaging in detecting residual breast cancer after neoadjuvant therapy. J Natl Cancer Inst 105(5):321–333

    CAS  PubMed  Google Scholar 

  • Mazari FAK, Sharma N, Dodwell D, Horgan K (2018) Human Epidermal Growth Factor 2-positive breast cancer with mammographic microcalcification: relationship to pathologic complete response after neoadjuvant chemotherapy. Radiology 288(2):366–374

    PubMed  Google Scholar 

  • Niikura N, Tomotaki A, Miyata H, Iwamoto T, Kawai M, Anan K et al (2016) Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry. Ann Oncol 27(3):480–487

    CAS  PubMed  Google Scholar 

  • O’Grady S, Morgan MP (2018) Microcalcifications in breast cancer: from pathophysiology to diagnosis and prognosis. Biochim Biophys Acta Rev Cancer 1869(2):310–320

    CAS  PubMed  Google Scholar 

  • Okumura Y, Nishimura R, Nakatsukasa K, Yoshida A, Masuda N, Tanabe M et al (2015) Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence. Eur J Surg Oncol 41(4):548–552

    CAS  PubMed  Google Scholar 

  • Onishi T, Hayashi N, Theriault RL, Hortobagyi GN, Ueno NT (2010) Future directions of bone-targeted therapy for metastatic breast cancer. Nat Rev Clin Oncol 7(11):641–651

    CAS  PubMed  Google Scholar 

  • Pálka I, Ormándi K, Gaál S, Boda K, Kahán Z (2007) Casting-type calcifications on the mammogram suggest a higher probability of early relapse and death among high-risk breast cancer patients. Acta Oncol 46(8):1178–1183

    PubMed  Google Scholar 

  • Perez-Lopez R, Nava Rodrigues D, Figueiredo I, Mateo J, Collins DJ, Koh DM et al (2018) Multiparametric magnetic resonance imaging of prostate cancer bone disease: correlation with bone biopsy histological and molecular features. Invest Radiol 53(2):96–102

    PubMed  PubMed Central  Google Scholar 

  • Scimeca M, Giannini E, Antonacci C, Pistolese CA, Spagnoli LG, Bonanno E (2014) Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics. BMC Cancer 14:286

    PubMed  PubMed Central  Google Scholar 

  • Scott R, Stone N, Kendall C, Geraki K, Rogers K (2016) Relationships between pathology and crystal structure in breast calcifications: an in situ X-ray diffraction study in histological sections. NPJ Breast Cancer 2:16029

    PubMed  PubMed Central  Google Scholar 

  • Sickles E, d’Orsi C, Bassett L, Appleton C, Berg W, (2013) Burnside EJAB-Ra, breast imaging reporting, et al. Acr bi-rads® mammography. 5

  • Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72(1):7–33

    PubMed  Google Scholar 

  • Spring L, Greenup R, Niemierko A, Schapira L, Haddad S, Jimenez R et al (2017) Pathologic complete response after neoadjuvant chemotherapy and long-term outcomes among young women with breast cancer. J Natl Compr Canc Netw 15(10):1216–1223

    PubMed  Google Scholar 

  • Steenbruggen TG, van Ramshorst MS, Kok M, Linn SC, Smorenburg CH, Sonke GS (2017) Neoadjuvant therapy for breast cancer: established concepts and emerging strategies. Drugs 77(12):1313–1336

    CAS  PubMed  Google Scholar 

  • Tabár L, Dean PB, Tucker FL, Yen AM, Fann JC, Lin AT et al (2022) Breast cancers originating from the terminal ductal lobular units: In situ and invasive acinar adenocarcinoma of the breast. AAB Eur J Radiol 152:110323

    PubMed  Google Scholar 

  • Tanioka M, Sasaki M, Shimomura A, Fujishima M, Doi M, Matsuura K et al (2014) Pathologic complete response after neoadjuvant chemotherapy in HER2-overexpressing breast cancer according to hormonal receptor status. Breast 23(4):466–472

    PubMed  Google Scholar 

  • Taskin F, Kalayci CB, Tuncbilek N, Soydemir E, Kurt N, Kaya H et al (2021) The value of MRI contrast enhancement in biopsy decision of suspicious mammographic microcalcifications: a prospective multicenter study. Eur Radiol 31(3):1718–1726

    PubMed  Google Scholar 

  • Thompson BM, Chala LF, Shimizu C, Mano MS, Filassi JR, Geyer FC et al (2022) Pre-treatment MRI tumor features and post-treatment mammographic findings: may they contribute to refining the prediction of pathologic complete response in post-neoadjuvant breast cancer patients with radiologic complete response on MRI? Eur Radiol 32(3):1663–1675

    PubMed  Google Scholar 

  • Toss A, Palazzo J, Berger A, Guiles F, Sendecki JA, Simone N et al (2016) Clinical-pathological features and treatment modalities associated with recurrence in DCIS and micro-invasive carcinoma: who to treat more and who to treat less. Breast 29:223–230

    PubMed  Google Scholar 

  • Tot T (2015) Early (<10 mm) HER2-positive invasive breast carcinomas are associated with extensive diffuse high-grade DCIS: implications for preoperative mapping, extent of surgical intervention, and disease-free survival. Ann Surg Oncol 22(8):2532–2539

    PubMed  Google Scholar 

  • Tsau HS, Yen AM, Fann JC, Wu WY, Yu CP, Chen SL et al (2015) Mammographic tumour appearance and triple-negative breast cancer associated with long-term prognosis of breast cancer death: a Swedish Cohort Study. Cancer Epidemiol 39(2):200–208

    PubMed  Google Scholar 

  • von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804

    Google Scholar 

  • Wang N, Reeves KJ, Brown HK, Fowles AC, Docherty FE, Ottewell PD et al (2015) The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer. J Exp Clin Cancer Res 34:124

    CAS  PubMed  PubMed Central  Google Scholar 

  • Weigel S, Decker T, Korsching E, Hungermann D, Böcker W, Heindel W (2010) Calcifications in digital mammographic screening: improvement of early detection of invasive breast cancers? Radiology 255(3):738–745

    PubMed  Google Scholar 

  • Weiss A, Lee KC, Romero Y, Ward E, Kim Y, Ojeda-Fournier H et al (2014) Calcifications on mammogram do not correlate with tumor size after neoadjuvant chemotherapy. Ann Surg Oncol 21(10):3310–3316

    PubMed  Google Scholar 

  • Whitworth P, Beitsch P, Mislowsky A, Pellicane JV, Nash C, Murray M et al (2017) Chemosensitivity and endocrine sensitivity in clinical luminal breast cancer patients in the prospective neoadjuvant breast registry symphony trial (NBRST) predicted by molecular subtyping. Ann Surg Oncol 24(3):669–675

    PubMed  Google Scholar 

  • Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013

    PubMed  Google Scholar 

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Acknowledgements

We thank all the members of the institution for their help in discussions and for providing technical assistance.

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The funder played no role in determining the content of the manuscript or in the decision regarding whether to submit the manuscript for publication.

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Authors

Contributions

YH and LM contributed to data management and designed the research. MW, ZL, ML, CW, and LJ contributed to software use, imaging processing, and methodology. XZ contributed to pathology analysis. YH writing the original manuscript. HZ and XZ reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Hui Zeng or Xiaoling Zhang.

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The authors declare no competing financial or non-financial interests.

Ethical approval

This study involved human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-Sen University (No.2020–536) and Southern Hospital of Southern Medical University (NFEC-201706-K3-01) and waived written informed consent.

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Hu, Y., Mao, L., Wang, M. et al. New insights into breast microcalcification for poor prognosis: NACT cohort and bone metastasis evaluation cohort. J Cancer Res Clin Oncol 149, 7285–7297 (2023). https://doi.org/10.1007/s00432-023-04668-4

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  • DOI: https://doi.org/10.1007/s00432-023-04668-4

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