Top

Published in:

01-10-2010 | American Society of Breast Surgeons

Molecular Detection of Micrometastatic Breast Cancer in Histopathology—Negative Axillary Lymph Nodes Fails to Predict Breast Cancer Recurrence: A Final Analysis of a Prospective Multi-Institutional Cohort Study

Authors: Carla Suzanne Fisher, MD, David J. Cole, MD, Michael Mitas, PhD, Elizabeth Garrett-Meyer, PhD, John S. Metcalf, MD, William E. Gillanders, MD, Kaidi Mikhitarian, MD, Marshall M. Urist, MD, G. Bruce Mann, MD, Gerard Doherty, MD, Virginia M. Herrmann, MD, Arnold D. Hill, MD, Oleg Eremin, MD, Mohamed El-Sheemy, MD, PhD, Richard K. Orr, MD, Alvaro A. Valle, MD, Michael A. Henderson, MD, Robert L. Dewitty, MD, Sonia L. Sugg, MD, Eric Frykberg, MD, Karen Yeh, MD, Richard M. Bell, MD, Megan K. Baker, MD

Published in: Annals of Surgical Oncology | Special Issue 3/2010

Abstract

Background

To address the clinical relevance of molecular detection of occult breast cancer in sentinel lymph nodes and nonsentinel axillary lymph nodes (ALN), we initiated the Minimally Invasive Molecular Staging of Breast Cancer (MIMS) trial, a multi-institutional prospective cohort study. This trial represents the first prospective cohort study in which a multimarker, real-time reverse transcription polymerase chain reaction (RT-PCR) analysis was applied to the detection of breast cancer micrometastases in ALN.

Materials and Methods

Sentinel and/or nonsentinel ALN from 501 breast cancer subjects with T1–T3 primary tumors were analyzed by standard histopathology and multimarker, real-time RT-PCR analysis. Seven breast cancer-associated genes (mam, mamB, PIP, CK19, muc1, PSE, and CEA) known to be overexpressed in metastatic breast cancer compared with control lymph nodes were used. Follow-up data were collected for 5 years.

Results

Of the 501 breast cancer subjects enrolled, 348 were node negative and completed the 5-year follow-up. Of these patients (n = 94), 27% demonstrated evidence of molecular overexpression. The 5-year relapse-free survival rate was 95.4% (95% confidence interval [95% CI], 92.4–97.2%). No single gene or combination of study genes was predictive of recurrence.

Conclusions

The genes in this study panel failed to be predictive of clinical relapse. This may be a function of several factors: the low event rate at 5 years, the particular gene set, the methodology used for detection/analysis or that our original hypothesis was wrong and that the presence of positive marker signal by real-time RT-PCR is not associated with a worsened clinical outcome.

Donegan WL. Tumor-related prognostic factors for breast cancer. CA Cancer J Clin. 1997;47:28–51.CrossRefPubMed

Goldhirsch A, Glick JH, Gelber RD, Coates AS, Senn HJ. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh international conference on adjuvant therapy of primary breast cancer. J Clin Oncol. 2001;19:3817–27.PubMed

Woo CS, Silberman H, Nakamura SK, Ye W, Sposto R, Colburn W, et al. Lymph node status combined with lymphovascular invasion creates a more powerful tool for predicting outcome in patients with invasive breast cancer. Am J Surg. 2002;284:337–40.CrossRef

Cummings MC, Walsh MD, Hohn BG, Bennett IC, Wright RG, McGuckin MA. Occult axillary lymph node metastases in breast cancer do matter: results of 10-year survival analysis. Am J Surg Pathol. 2002;26:1286–95.CrossRefPubMed

Rosen PP, Saigo P, Jr. OB, Weathers E, DePalo A. Predictors of recurrence in stage 1 (T1N1M0) breast carcinoma. Ann Surg. 1981;193:15–20.

de Mascarel I, Bonichon I, Coindre J, Trojani M. Prognostic significance of breast cancer axillary lymph node micrometastases assessed by two special techniques: reevaluation with longer follow-up. Br J Cancer. 1992;66:523–7.PubMed

McGuckin MA, Cummings MC, Walsh MD, Hohn BG, Bennett IC, Wright RG. Occult axillary node metastases in breast cancer: their detection and prognostic significance. Br J Cancer. 1996;73:88–95.PubMed

Sedmak DD, Meineke TA, Knechtges DS. Detection of metastatic breast carcinoma with monoclonal antibodies to cytokeratins. Arch Pathol Lab Med. 1989;113:786–9.PubMed

de Boer M, van Deurzen C, van Dijck J, Borm GF, van Diest PJ, Adang EM, et al. Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009;361:653–63.CrossRefPubMed

10.

de Boer M, van Dijck JAAM, Bult P, Borm GF, Tjan-Heijnen VC. Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst. 2010;102:410–25.

11.

Lockett MA, Baron PL, O’Brien PH, Elliott BM, Robison JG, Maitre N, et al. Detection of occult breast cancer micrometastases in axillary lymph nodes using a multi-marker reverse transcriptase-polymerase chain reaction panel. J Am Coll Surg. 1998;187:9–16.CrossRefPubMed

12.

Lockett MA, Metcalf JS, Baron PL, O’Brien PH, Elliott BM, Robison JG, et al. Efficacy of reverse transcriptase-polymerase chain reaction screening for micrometastatic disease in axillary lymph nodes of breast cancer patients. Am Surg. 1998;64:539–43.PubMed

13.

Schoenfeld A, Luqmani Y, Smith D, O’Reilly S, Shousha S, Sinnett HD, et al. Detection of breast cancer micrometastases in axillary lymph nodes by using polymerase chain reaction. Cancer Res. 1994;54:2986–90.PubMed

14.

Mori M, Mimori K, Inoue H, Barnard GF, Tsuji K, Nanbara S, et al. Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res. 1995;74:3417–20.

15.

Datta YH, Adams PT, Drobyski WR, Ethier SP, Terry VH, Roth MS. Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction. J Clin Oncol. 1994;12:475–82.PubMed

16.

Bostick PJ, Chatterjee S, Chi DD, Huynh KT, Giuliano AE, Cote R, et al. Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. J Clin Oncol. 1998;16:2632–40.PubMed

17.

Eltahir EM, Mallinson DS, Birnie GD, Hagan C, George WD, Purushotham AD. Putative markers for the detection of breast carcinoma cells in blood. Br J Cancer. 1998;77:1203–7.PubMed

18.

Giesing M, Austrup F, Bockmann B, Driesel G, Eder C, Kusiak I, et al. Independent prognostication and therapy monitoring of breast cancer patients by DNA/RNA typing of minimal residual cancer cells. Int J Biol Markers. 2000;15:94–9.PubMed

19.

Goeminne JC, Guillaume T, Salmon M, Machiels JP, D’Hondt V, Symann M. Unreliability of carcinoembryonic antigen (CEA) reverse transcriptase-polymerase chain reaction (RT-PCR) in detecting contaminating breast cancer cells in peripheral blood stem cells due to induction of CEA by growth factors. Bone Marrow Transplant. 1999;24:769–75.CrossRefPubMed

20.

Lopez-Guerrero JA, Gilabert PB, Gonzalez EB, Sanz Alonso MA, Perez JP, Talens AS, et al. Use of reverse-transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen, cytokeratin 19, and maspin in the detection of tumor cells in leukapheresis products from patients with breast cancer: comparison with immunocytochemistry. J Hematother. 1999;8:53–61.CrossRefPubMed

21.

Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997;89:139–47.CrossRefPubMed

22.

Mitas M, Mikhitarian K, Walters C, Baron PL, Elliott BM, Brothers TE, et al. Quantitative real-time RT-PCR detection of breast cancer micrometastasis using a multigene marker panel. Int J Cancer. 2001;93:162–71.CrossRefPubMed

23.

Mitas M, Mikhitarian K, Hoover L, Lockett MA, Kelley L, Hill A, Gillanders WE, et al. Prostate-specific Ets (PSE) factor: a novel marker for detection of metastatic breast cancer in axillary lymph nodes. Br J Cancer. 2002;86:899–904.CrossRefPubMed

24.

Veys I, Durbecq V, Majjaj S, Schobbens JC, Noterman D, Sirtaine N, et al. Eighteen months clinical experience with the GeneSearch breast lymph node assay. Am J Surg. 2009;198:203–9.CrossRefPubMed

25.

Tafe L, Schwab M, Lefferts JA, Wells WA, Tsongalis GJ. A validation study of a new molecular diagnostic assay: The Dartmouth-Hitchcock Medical Center experience with the GeneSearch BLN assay in breast sentinel lymph nodes. Exp Mol Pathol. 2010;88:1–6.CrossRefPubMed

26.

Gillanders WE, Mikhitarian K, Hebert R, Mauldin PD, Palesch Y, Walters C, et al. Molecular detection of micrometastatic breast cancer in histopathology-negative axillary lymph nodes correlates with traditional predictors of prognosis. Ann Surg. 2004;239:828–40.CrossRefPubMed

27.

Noguchi S, Aihara R, Motomura K, Inaji H, Imaoka S, Koyama H. Histological characteristics of breast cancer patients with occult lymph node metastases detected by keratin 19 mRNA reverse transcriptase-polymerase chain reaction. Cancer. 1996;78:1235–40.CrossRefPubMed

28.

Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007;25:486–92.CrossRefPubMed

29.

Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (intergroup exemestane study): a randomised controlled trial. Lancet. 2007;369:559–70.CrossRefPubMed

30.

Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365:60–2.CrossRefPubMed

31.

Abdul-Rasool S, Kidson S, Panieri E, Dent D, Pillay K, Hanekom GS. An evaluation of molecular markers for improved detection of breast cancer metastases in sentinel nodes. J Clin Pathol. 2006;59:289–97.CrossRefPubMed

32.

Hughes SJ, Xi L, Raja S, Gooding W, Cole DJ, Gillanders WE, et al. A rapid, fully automated, molecular-based assay accurately analyzes sentinel lymph nodes for the presence of metastatic breast cancer. Ann Surg. 2006;243:389–98.CrossRefPubMed

33.

Martin Martinez MDM, Veys I, Majjaj S, Lespagnard L, Schobbens JC, Rouas G, et al. Clinical validation of a molecular assay for intra-operative detection of metastases in breast sentinel lymph nodes. Eur J Surg Oncol. 2009;35:387–92.PubMed

34.

Backus J, Laughlin T, Wang Y, Belly R, White R, Baden J, et al. Identification and characterization of optimal gene expression markers for detection of breast cancer metastasis. J Mol Diagn. 2005;7:327–36.PubMed

35.

Zehentner BK, Dillon DC, Jiang Y, Xu J, Bennington A, Molesh DA, et al. Application of a multigene reverse transcription-PCR assay for detection of mammaglobin and complementary transcribed genes in breast cancer lymph nodes. Clin Chem. 2002;48:1225–31.PubMed

36.

Manzotti M, Dell’Orto P, Maisonneuve P, Zurrida S, Mazzarol G, Viale G. Reverse transcription-polymerase chain reaction assay for multiple mRNA markers in the detection of breast cancer metastases in sentinel lymph nodes. Int J Cancer. 2001;95:307–12.CrossRefPubMed

37.

Min CJ, Tafra L, Verbanac KM. Identification of superior markers for PCR detection of breast cancer metastases in sentinel lymph nodes. Cancer Res. 1998;58:4581–4.PubMed

38.

Marchetti A, Buttitta F, Bertacca G, Zavaglia K, Bevilacqua G, Angelucci D, et al. mRNA markers of breast cancer nodal metastases: comparison between mammaglobin and carcinoembryonic antigen in 248 patients. J Pathol. 2001;195:186–90.CrossRefPubMed

39.

Watson MA, Dintzis S, Darrow CM, Voss LE, DiPersio J, Jensen R, et al. Mammaglobin expression in primary, metastatic, and occult breast cancer. Cancer Res. 1999;59:3028–31.PubMed

40.

Leygue E, Snell L, Dotzlaw H, Hole K, Troup S, Hiller-Hitchcock T, et al. Mammaglobin, a potential marker of breast cancer nodal metastasis. J Pathol. 1999;189:28–33.CrossRefPubMed

41.

Viale G, Dell’Orto P, Biasi M, Stufano V, De Brito Lima LN, et al. Comparative evaluation of an extensive histopathologic examination and a real-time reverse-transcription-polymerase chain reaction assay for mammaglobin and cytokeratin 19 on axillary sentinel lymph nodes of breast carcinoma patients. Ann Surg. 2008;247:136–42.CrossRefPubMed

42.

Blumencranz P, Whitworth P, Deck K, Rosenberg A, Reintgen D, Beitsch P, et al. Scientific Impact Recognition Award. Sentinel node staging for breast cancer: intraoperative molecular pathology overcomes conventional histologic sampling errors. Am J Surg. 2007;194:426–32.CrossRefPubMed

Title: Molecular Detection of Micrometastatic Breast Cancer in Histopathology—Negative Axillary Lymph Nodes Fails to Predict Breast Cancer Recurrence: A Final Analysis of a Prospective Multi-Institutional Cohort Study
Authors: Carla Suzanne Fisher, MD
David J. Cole, MD
Michael Mitas, PhD
Elizabeth Garrett-Meyer, PhD
John S. Metcalf, MD
William E. Gillanders, MD
Kaidi Mikhitarian, MD
Marshall M. Urist, MD
G. Bruce Mann, MD
Gerard Doherty, MD
Virginia M. Herrmann, MD
Arnold D. Hill, MD
Oleg Eremin, MD
Mohamed El-Sheemy, MD, PhD
Richard K. Orr, MD
Alvaro A. Valle, MD
Michael A. Henderson, MD
Robert L. Dewitty, MD
Sonia L. Sugg, MD
Eric Frykberg, MD
Karen Yeh, MD
Richard M. Bell, MD
Megan K. Baker, MD
Publication date: 01-10-2010
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue Special Issue 3/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-010-1258-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Molecular Detection of Micrometastatic Breast Cancer in Histopathology—Negative Axillary Lymph Nodes Fails to Predict Breast Cancer Recurrence: A Final Analysis of a Prospective Multi-Institutional Cohort Study

Abstract

Background

Materials and Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Materials and Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Special Issue 3/2010

Increase in Contralateral Prophylactic Mastectomy: Echoes of a Bygone Era?

Presidential Address: 2010. The American Society of Breast Surgeons. There’s no “Boring” in Breast Surgery!!

Are Percutaneous Biopsy Rates a Reasonable Quality Measure in Breast Cancer Management?

Micrometastatic Disease and Isolated Tumor Cells as a Predictor for Additional Breast Cancer Axillary Metastatic Burden

Single-Center Long-Term Follow-Up After Intraoperative Radiotherapy as a Boost During Breast-Conserving Surgery Using Low-Kilovoltage X-Rays