Clinical, morphological and molecular predictors of metastatic regional lymph node involvement in breast cancer patients

Background. The article presents the results of our study aimed to identify predictors of metastatic regional lymph node involvement based on the biological characteristics of the primary tumor.

Materials and methods. The study involved 200 female patients with histologically verified unicentric invasive breast cancer (BC) T1-4N0-3M0 who were treated in the state healthcare institution Regional Clinical Cancer Center of Ulyanovsk between 2012 and 2015. Clinical, morphological and molecular parameters of the tumor were analyzed.

Results. A unifactorial statistical analysis has shown that the size of the primary tumor node (p = 0.027), histological variant (p < 0.001), malignancy grade (p = 0.027), total malignancy score (TMS, p < 0.001), lymphovascular invasion status (p < 0.001), and HER2-status (p = 0.0002) are predictors of metastatic lymph node involvement. No significant relationship was found between age (p = 0.118), estrogen receptor status (ER, p = 0.092), progesterone receptor status (PR, p = 0.081), Ki-67 index (p = 0.132), molecular subtype of the tumor (p = 0.213) and presence of axillary lymph node metastases.

Conclusion. The primary tumor size, histological variant, malignancy grade, TMS, lymphovascular invasion, and HER2-status are independent risk factors of metastatic involvement of regional lymph nodes and may be used by clinicians for axillary surgery planning in BC patients.

1. Злокачественные новообразования в России в 2017 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, Г.В. Петровой — М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2018. 250 с.

2. Petrek J.A., Senie R.T., Peters M., Rosen P.P. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 2001;92 (6):1368-77.

3. Silberman A.W., McVay C., Cohen J.S., Altura J.F., Brackert S., Sarna G.P. et al. Comparative morbidity of axillary lymph node dissection and the sentinel lymph node technique: Implications for patients with breast cancer. Ann Surg 2004; 240 (1): 1-6.

4. Wilke L.G., McCall L.M., Posther K.E., Whitworth P.W., Reintgen D.S., Leitch A.M., et al. Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group trial. Ann Surg Oncol 2006;13 (4): 491-500.

5. Mansel R.E., Fallowfield L., Kissin M., Goyal A., Newcombe R.G., Dixon J.M., et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC Trial. J Natl Cancer Inst 2006; 98 (9): 599-609.

6. Fisher B., Jeong J.H., Anderson S., Bryant J., Fisher E.R., Wolmark N. Twenty-Five-Year Follow-up of a Randomized Trial Comparing Radical Mastectomy, Total Mastectomy, and Total Mastectomy Followed by Irradiation. N. Engl. Med 2002; 347 (8): 567-575.

7. Orr R.K. The impact of prophylactic axillary node dissection on breast cancer survival: a Bayesian meta-analysis. Ann Surg Oncol 1999; 6109: 116-27.

8. Giuliano A.E., Hunt K.K., Ballman K.V., Beitsch P.D., Whitworth P.W., Blumencranz P.W., et al. Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis. JAMA. 2011; 305 (6): 569-575.

9. Shah-Khan M., Boughey J.C. Evolution of axillary nodal staging in breast cancer: clinical implications of the ACOSOG Z0011 trial. Cancer Control 2012; 19: 267-276.

10. Занкин В.В., Родионов В.В., Хайруллин Р.М., Кометова В.В. Гистологическая степень злокачественности эпителиальных опухолей как фактор прогноза их рецидивирования и метастазирования после радикального лечения (взгляд патоморфолога на клинические проблемы). Материалы VI Российской научно-практической конференции «Модниковские чтения». Ульяновск, 2009; 48-50.

11. Кометова В.В., Родионов В.В., Занкин В.В., Даньшина А.В., Дергунова Ю.А. О корреляции пролиферативного индекса Ki-67 с некоторыми клинико-морфологическими показателями первичной опухоли и регионарных метастазов у пациенток с инвазивным раком молочной железы. Ульяновский медико-биологический журнал. 2014, №4:18-20.

12. Родионов В.В, Занкин В.В., Аюпова С.Р., Алиева Р.М. Клинико-морфологические предикторы метастатического поражения регионарных лимфоузлов у больных раком молочной железы. Ульяновский медико-биологический журнал. 2012, № 3:85-88.

13. Родионов В.В., Панченко С.В., Идрисова С.Р., Кометова В.В., Савинов Ю.Г. Номограмма для прогнозирования вероятности метастатического поражения регионарных лимфатических узлов у больных раком молочной железы. Вопросы онкологии. 2015; 61 (3): 435-438.

14. Kometova V., Rodionov V., Dergunova Y., Rodionova M. The expression and significance of Ki-67 in the primary tumour and lymph nodes metastases in breast cancer patients. Virchow Arch. 2016; 469 (suppl1): 50.

15. Kometova V., Rodionov V., Idrisova S., Dergunova Y., Rodionova M. Pathological predictors of axillary lymph node metastases in women with breast cancer. Virchow Arch. 2017; 471 (suppl1): 57.

16. Kometova V., Rodionov V., Rodionova M., Dergunova Y., Panchenko S. New prognostic integrated pathological index in breast cancer patients. Virchow Arch. 2017; 471 (suppl1): 57

17. Rodionov V., Cometova V., Panchenko S. A new nomogram to predict axillary metastasis in breast cancer patients without axillary surgery. Cancer research. 2015; 75 (9): Р2-01-30

18. Fisher B., Slack N.H., Bross I.D. Cancer of the breast: size of neoplasm and prognosis. Cancer 1969; 24 (5): 1071-80.

19. Chua B., Ung O., Taylor R. Boyages J. Frequency and predictors of axillary lymph node metastases in invasive breast cancer.ANZ JSurg 2001;71 (12):723-8.

20. Chen M., Palleschi S., Khoynezhad A. Gecelter G., Marini C.P., Simms H.H. Role of primary breast cancer characteristics in predicting positive sentinel lymph node biopsy results: a multivariate analysis. Arch Surg 2002;137 (5): 606-9.

21. Harden S.P., Neal A.J., Al Nasiri N., Ashley S., Querci della Rovere G. Predicting axillary lymph node metastases in patients with T1 infiltrating ductal carcinoma of the breast. Breast 2001; 10 (2): 155-9.

22. Brenin D.R., Manasseh D.M., El-Tamer M., Troxel A., Schnabel F., Ditkoff B.A., et al. Factors correlating with lymph node metastases in patients with T1 breast cancer. Ann Surg Oncol 2001; 8 (5):432-7.

23. Anan K., Mitsuyama S., Tamae K., Nishihara K., Iwashita T., Abe Y., et al. Axillary lymph node metastases in patients with small carcinomas of the breast: Is accurate prediction possible? Eur J Surg 2000; 166 (8): 610-5.

24. Amrut V. Ashturkar, Gayatri S. Pathak., Sanjay D. Deshmukh, Harshal T. Pandave. Factors Predicting the Axillary Lymph Node Metastasis in Breast Cancer: Is Axillary Node Clearance Indicated in Every Breast Cancer Patient? Indian J Surg. 2011; 73 (5): 331-335.

25. Qiu S.Q., Zeng H.C., Zhang F., Chen C., Huang W.H., Pleijhuis R.G., et al. A nomogram to predict the probability of axillary lymph node metastasis in early breast cancer patients with positive axillary ultrasound. Sci Rep 2016; 6: 21196.

26. Papadatos G., Rangan A. M., Psarianos T., Ung O., Taylor R., Boyages J. Probability of axillary node involvement in patients with tubular carcinoma of the breast. Br J Surg 2001; 88 (6): 860-4.

27. Wiechmann L., Sampson M., Stempel M., Jacks L.M., Patil S.M., King T., et al. Presenting features of breast cancer differ by molecular subtype. Ann Surg Oncol 2009; 16 (10): 2705-10.

28. Klevesath M. B., Pantel K., Agbaje O., Provenzano E., Wishart G.C., Gough P., et al. Patterns of metastatic spread in early breast cancer. Breast 2013;22 (4):449-54.

29. Viale G., Zurrida S., Maiorano E., Mazzarol G., Pruneri G., Paganelli G., et al. Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution. Cancer 2005; 103 (3): 492-500.

30. Zhang S., Zhang D., Yi S., Gong M., Lu C., Cai Y., et al. The relationship of lymphatic vessel density, lymphovascular invasion, and lymph node metastasis in breast cancer: a systematic review and meta-analysis. Oncotarget 2017; 8 (2): 2863-73.

31. Ugras S., Stempel M., Patil S., Morrow M. Estrogen receptor, progesterone receptor, and HER2 status predict lymphovascular invasion and lymph node involvement. Ann Surg Oncol 2014; 21 (12): 3780-86.

32. Crabb S. J., Cheang M. C., Leung S., Immonen T., Nielsen T.O., Huntsman D.D., et al. Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer. Clin Breast Cancer 2008; 8 (3): 249-56.

33. Dihge L., Bendahl P. O., Ryden L. Nomograms for preoperative prediction of axillary nodal status in breast cancer. Br J Surg 2017; 104 (11): 1494-505.

34. Jones T., Neboori H., Wu H. et al. Estrogen receptor, progesterone receptor, and HER2 status predict lymphovascular invasion and lymph node involvement? Ann Surg Oncol 2013; 20: 2866-72