Korean J Radiol.  2019 Jan;20(1):69-82. 10.3348/kjr.2018.0231.

Introduction of a New Staging System of Breast Cancer for Radiologists: An Emphasis on the Prognostic Stage

• Koh J
• Kim MJ

• KMID: 2429921
• DOI: http://doi.org/10.3348/kjr.2018.0231

Abstract

In 2017, the American Joint Committee on Cancer announced the 8th edition of its cancer staging system. For breast cancer, the most significant change in the staging system is the incorporation of biomarkers into the anatomic staging to create prognostic stages. Different prognostic stages are assigned to tumors with the same anatomic stages according to the tumor grade, hormone receptor (estrogen receptor; progesterone receptor) status, and HER2 status. A Clinical Prognostic Stage is assigned to all patients regardless of the type of therapy used; in contrast, a Pathologic Prognosis Stage is assigned to patients in whom surgery is the initial treatment. In a few situations, low Oncotype DX recurrence scores can change the prognostic stage. The radiologists need to understand the importance of the biologic factors that can influence cancer staging.

Keyword

Breast neoplasm; TNM stage; Biomarker; AJCC; Prognostic stage

MeSH Terms

Biological Factors
Biomarkers
Breast Neoplasms*
Breast*
Humans
Joints
Neoplasm Staging
Progesterone
Prognosis
Recurrence
Biological Factors
Biomarkers
Progesterone

Figure

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  Fig. 1 Measurement of tumor size.Maximum tumor size measures 4.3 cm on ultrasound image (arrow). It also measures 4.3 cm pathologically. Therefore, both clinical and pathologic T category is T2. T = tumor

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  Fig. 2 Determination of T categories.A. Maximum size of largest tumor is measured (solid line), but size of smaller tumors is not added (dotted line). B. Magnetic resonance maximum intensity projection image demonstrates multiple synchronous tumors in breast. Maximum invasive size of largest tumor is 2.4 cm (arrow), and size of smaller tumors (arrowheads) is not added. Therefore, cT2 (m) is designated for T stage.

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  Fig. 3 T4b breast cancer.MRI shows primary breast cancer in left upper breast (arrowheads). Separate skin nodule is identified at left upper outer part, which qualifies as T4b (arrow). MRI = magnetic resonance imaging

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  Fig. 4 T4c breast cancer.A. MRI shows left breast cancer with skin ulceration (arrow) and rib extension (arrowheads). B. Physical examination shows ulceration extending to less than one third of breast, which does not meet definition of IBC. IBC = inflammatory breast cancer

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  Fig. 5 Left IBC (T4d).A. MRI shows diffuse skin enhancement (arrowheads) and chest wall extension (arrow). B. Physical examination of left breast shows erythema and peau d'orange (orange peel skin) appearance of skin, which meets definition of IBC.

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  Fig. 6 cN3 category.A, B. cN3a: Ultrasound images from right breast cancer case show enlarged hypoechoic lymph nodes with loss of fatty hilum not only in right axilla (A) level II (arrows), but also on (B) level III (arrow). Note pectoralis minor muscle (arrowheads), which is landmark for grouping axillary lymph nodes. C, D. cN3b: (C) MRI of case of cancer in right breast shows enlarged lymph nodes in right axilla (arrow). (D) Enlarged right internal mammary lymph node is also noted (arrowhead). E, F. cN3c: (E) Ultrasound of left breast cancer case shows enlarged lymph node in left axilla (arrow). (F) Enlarged left supraclavicular lymph node is also noted (arrowhead). AX = axilla

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  Fig. 7 Right breast cancer with lung metastasis (M1).On positron emission tomography-computed tomography, 10-cm cancerous mass is seen in right breast and multiple FDG uptakes are seen in right axillary lymph nodes (arrow); there are lung nodules with FDG uptake, suggesting lung metastasis (arrowhead). FDG = fludeoxyglucose, M = metastasis

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  Fig. 8 Size measurement after neoadjuvant chemotherapy.A. Initial MRI shows 4.3-cm irregular breast cancer in left breast (T2) (arrow). B. After neoadjuvant chemotherapy, cancer reduced to multiple small masses (arrowheads); largest one measures 10 mm (arrow). Therefore, post treatment T category is ycT1b (m).

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  Fig. 9 Patient with cancer in right breast with MRI before (A, B) and after neoadjuvant chemotherapy (C, D).A. Initial MRI shows 2.2-cm right breast cancer (arrow). B. Ipsilateral matted axillary lymph node enlargement is noted (arrows). Initial stage is T2N2aM0. C. After neoadjuvant chemotherapy, there is no residual mass. D. Axillary lymph nodes have disappeared, which suggests clinical CR (ycT0N0M0). Histopathologic evaluation shows absence of invasive carcinoma in breast and lymph nodes, indicating pathologic CR (ypT0N0M0). CR = complete response

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  Fig. 10 Clinical Prognostic Stage is assigned to all patients regardless of type of therapy given.ER− = estrogen receptor-negative, ER+ = ER-positive, G = grade, HER2− = HER2 negative, HER2+ = HER2-positive, mi = micrometastasis, PR− = progesterone receptor-negative, PR+ = PR-positive, Tis = in situ

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  Fig. 11 Pathologic Prognostic Stage is assigned to patients who received surgery as initial treatment.Additionally, pT1, pT2, pN0, M0, ER+, and HER2− cancers are assigned as Pathologic Prognostic Stage group IA when Oncotype DX recurrence score is less than 11.

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  Fig. 12 Right breast cancer with low histologic grade.A. MRI demonstrates breast cancer measuring 2.3 cm in upper breast (arrow). B. Ultrasound shows enlarged, right axillary lymph node with eccentric cortical thickening (arrow). After partial mastectomy, cancer measures 2.5 cm with two level-I lymph node metastases. Cancer is ER+/PR+ and HER2−. Histologic grade is 1, and anatomic stage is IIB (T2N1M0). However, due to low histologic grade and biomarker status, Clinical Prognostic Stage is IIA and Pathologic Prognostic Stage is IA.

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  Fig. 13 cT1N0M0 cancer.MRI shows that cancer measures 1.3 cm (arrow). There is no suspicious lymph node enlargement. Pathology shows 0.9-cm grade-2 carcinoma, but no hormone receptor or HER2 overexpression is noted. Therefore, anatomic stage is IA (T1N0M0), but it is triple negative cancer; thus, Clinical and Pathologic Prognostic Stages are higher, IB.

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  Fig. 14 cT2N0M0 cancer.MRI shows 3.7-cm enhancing cancer (arrow). No axillary metastasis is found. Anatomic stage is IIA. Tumor grade is 3, and hormone receptor and HER2 expressions are negative. This tumor has high histologic grade and is triple-negative; therefore, Clinical Prognostic Stage is higher, IIB.

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  Fig. 15 cT3N1M0 cancer downgraded by prognostic stage.A. Ultrasound image indicates complex cystic and solid mass in left lower outer breast (arrows). B. Left axillary ultrasound image shows cortically thickened lymph node (arrow). Anatomic stage is IIIA. Tumor grade is 1, ER and PR expression are found, and HER2 shows no overexpression; therefore, Clinical Prognostic Stage is IIA, and Pathologic Prognostic Stage is IB.

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  Fig. 16 cT2N0M0 cancer.Mediolateral oblique mammographic view demonstrates mass in left upper outer breast (arrowheads). Lymph nodes are not enlarged. Anatomic stage is IIA. Tumor is ER expression positive, HER2 shows no overexpression, and Oncotype Dx recurrence score is 5; therefore, Pathologic Prognostic Stage is IA.

Reference

1. Gabriel NH, James LC, Carl JD, Stephen BE, Elizabeth AM, Hope SR, et al. Breast. In : Mahul BA, editor. American Joint Committee on Cancer (AJCC). AJCC cancer staging manual. 8th ed. New York, NY: Springer;2017. p. 589–628.

2. Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast. 2015; 24(Suppl 2):S26–S35. PMID: 26253814.

3. Rezo A, Dahlstrom J, Shadbolt B, Rodins K, Zhang Y, Davis AJ. ACT & SENSW BCTG. Tumor size and survival in multicentric and multifocal breast cancer. Breast. 2011; 20:259–263. PMID: 21324695.

4. Morris EA, Schwartz LH, Drotman MB, Kim SJ, Tan LK, Liberman L, et al. Evaluation of pectoralis major muscle in patients with posterior breast tumors on breast MR images: early experience. Radiology. 2000; 214:67–72. PMID: 10644103.

5. Lee EJ, Han SH, Kang BJ, Kim SH. Imaging and pathologic characterization of the skin thickening or enhancement under the breast MRI. Investig Magn Reson Imaging. 2016; 20:9–26.

6. Chang S, Parker SL, Pham T, Buzdar AU, Hursting SD. Inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program of the National Cancer Institute, 1975–1992. Cancer. 1998; 82:2366–2372. PMID: 9635529.

7. Levine PH, Steinhorn SC, Ries LG, Aron JL. Inflammatory breast cancer: the experience of the surveillance, epidemiology, and end results (SEER) program. J Natl Cancer Inst. 1985; 74:291–297. PMID: 3856043.

8. Yang WT, Le-Petross HT, Macapinlac H, Carkaci S, Gonzalez-Angulo AM, Dawood S, et al. Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings. Breast Cancer Res Treat. 2008; 109:417–426. PMID: 17653852.

9. Le-Petross HT, Cristofanilli M, Carkaci S, Krishnamurthy S, Jackson EF, Harrell RK, et al. MRI features of inflammatory breast cancer. AJR Am J Roentgenol. 2011; 197:W769–W776. PMID: 21940550.

10. Alvarez S, Añorbe E, Alcorta P, López F, Alonso I, Cortés J. Role of sonography in the diagnosis of axillary lymph node metastases in breast cancer: a systematic review. AJR Am J Roentgenol. 2006; 186:1342–1348. PMID: 16632729.

11. Patel T, Given-Wilson RM, Thomas V. The clinical importance of axillary lymphadenopathy detected on screening mammography: revisited. Clin Radiol. 2005; 60:64–71. PMID: 15642295.

12. Mortellaro VE, Marshall J, Singer L, Hochwald SN, Chang M, Copeland EM, et al. Magnetic resonance imaging for axillary staging in patients with breast cancer. J Magn Reson Imaging. 2009; 30:309–312. PMID: 19466713.

13. Valente SA, Levine GM, Silverstein MJ, Rayhanabad JA, Weng-Grumley JG, Ji L, et al. Accuracy of predicting axillary lymph node positivity by physical examination, mammography, ultrasonography, and magnetic resonance imaging. Ann Surg Oncol. 2012; 19:1825–1830. PMID: 22227922.

14. Yoshimura G, Sakurai T, Oura S, Suzuma T, Tamaki T, Umemura T, et al. Evaluation of axillary lymph node status in breast cancer with MRI. Breast Cancer. 1999; 6:249–258. PMID: 11091725.

15. Giuliano AE, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch AM, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg. 2010; 252:426–432. discussion 432-433. PMID: 20739842.

16. Humphrey KL, Saksena MA, Freer PE, Smith BL, Rafferty EA. To do or not to do: axillary nodal evaluation after ACOSOG Z0011 trial. Radiographics. 2014; 34:1807–1816. PMID: 25384280.

17. Verheuvel NC, van den Hoven I, Ooms HW, Voogd AC, Roumen RM. The role of ultrasound-guided lymph node biopsy in axillary staging of invasive breast cancer in the post-ACOSOG Z0011 trial era. Ann Surg Oncol. 2015; 22:409–415. PMID: 25205303.

18. Farrell TP, Adams NC, Stenson M, Carroll PA, Griffin M, Connolly EM, et al. The Z0011 trial: is this the end of axillary ultrasound in the pre-operative assessment of breast cancer patients? Eur Radiol. 2015; 25:2682–2687. PMID: 25740803.

19. Patanaphan V, Salazar OM, Risco R. Breast cancer: metastatic patterns and their prognosis. South Med J. 1988; 81:1109–1112. PMID: 3420442.

20. Aebi S, Davidson T, Gruber G, Castiglione M. ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21(Suppl 5):v9–v14. PMID: 20555111.

21. Rapoport BL, Demetriou GS, Moodley SD, Benn CA. When and how do I use neoadjuvant chemotherapy for breast cancer? Curr Treat Options Oncol. 2014; 15:86–98. PMID: 24306808.

22. Yi M, Mittendorf EA, Cormier JN, Buchholz TA, Bilimoria K, Sahin AA, et al. Novel staging system for predicting disease-specific survival in patients with breast cancer treated with surgery as the first intervention: time to modify the current American Joint Committee on Cancer staging system. J Clin Oncol. 2011; 29:4654–4661. PMID: 22084362.

23. Schwartz AM, Henson DE, Chen D, Rajamarthandan S. Histologic grade remains a prognostic factor for breast cancer regardless of the number of positive lymph nodes and tumor size: a study of 161 708 cases of breast cancer from the SEER Program. Arch Pathol Lab Med. 2014; 138:1048–1052. PMID: 25076293.

24. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991; 19:403–410. PMID: 1757079.

25. Elston EW, Ellis IO. Method for grading breast cancer. J Clin Pathol. 1993; 46:189–190.

26. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011; 378:771–784. PMID: 21802721.

27. Barnes DM, Harris WH, Smith P, Millis RR, Rubens RD. Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer. 1996; 74:1445–1451. PMID: 8912543.

28. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235:177–182. PMID: 3798106.

29. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009; 14:320–368. PMID: 19346299.

30. Rosenthal SI, Depowski PL, Sheehan CE, Ross JS. Comparison of HER-2/neu oncogene amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer. Appl Immunohistochem Mol Morphol. 2002; 10:40–46. PMID: 11893034.

31. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365:1273–1283. PMID: 21991949.

32. Moasser MM, Krop IE. The evolving landscape of HER2 targeting in breast cancer. JAMA Oncol. 2015; 1:1154–1161. PMID: 26204261.

33. Gerdes J, Schwab U, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer. 1983; 31:13–20. PMID: 6339421.

34. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Panel Members. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015; 26:1533–1546. PMID: 25939896.

35. Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003; 95:142–153. PMID: 12529347.

36. Eiermann W, Rezai M, Kümmel S, Kühn T, Warm M, Friedrichs K, et al. The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use. Ann Oncol. 2013; 24:618–624. PMID: 23136233.

37. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015; 373:2005–2014. PMID: 26412349.

38. Stemmer S, Steiner M, Rizel S, Ben-Baruch N, Soussan-Gutman L, Rosengarten O, et al. 1963 first prospective outcome data in 930 patients with more than 5 year median follow up in whom treatment decisions in clinical practice have been made incorporating the 21-gene recurrence score. European Journal of Cancer. 2015; 51:S321.

39. Stemmer S, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, et al. Abstract P5-08-02: real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. Cancer Research. 2016; 76(4 Suppl):Abstract nr P5-08-02.

40. Gluz O, Nitz UA, Christgen M, Kates RE, Shak S, Clemens M, et al. West German Study Group phase III planB trial: first prospective outcome data for the 21-gene recurrence score assay and concordance of prognostic markers by central and local pathology assessment. J Clin Oncol. 2016; 34:2341–2349. PMID: 26926676.

41. Petkov VI, Miller DP, Howlader N, Gliner N, Howe W, Schussler N, et al. Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study. NPJ Breast Cancer. 2016; 2:16017. PMID: 28721379.

42. Drukker CA, Bueno-de-Mesquita JM, Retèl VP, van Harten WH, van Tinteren H, Wesseling J, et al. A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study. Int J Cancer. 2013; 133:929–936. PMID: 23371464.

43. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, et al. EP Investigators. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res. 2011; 17:6012–6020. PMID: 21807638.

44. Dubsky P, Filipits M, Jakesz R, Rudas M, Singer CF, Greil R, et al. Austrian Breast and Colorectal Cancer Study Group (ABCSG). EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer. Ann Oncol. 2013; 24:640–647. PMID: 23035151.

45. Filipits M, Nielsen TO, Rudas M, Greil R, Stöger H, Jakesz R, et al. Austrian Breast and Colorectal Cancer Study Group. The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer. Clin Cancer Res. 2014; 20:1298–1305. PMID: 24520097.

46. Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, et al. Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol. 2015; 33:916–922. PMID: 25332252.

47. Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol. 2013; 14:1067–1076. PMID: 24035531.

48. Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, et al. Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clin Cancer Res. 2013; 19:4196–4205. PMID: 23757354.

49. Mittendorf EA, Chavez-MacGregor M, Vila J, Yi M, Lichtensztajn DY, Clarke CA, et al. Bioscore: a staging system for breast cancer patients that reflects the prognostic significance of underlying tumor biology. Ann Surg Oncol. 2017; 24:3502–3509. PMID: 28726077.