Systematic Analysis of Breast Cancer Morphology Uncovers Stromal Features Associated with Survival

The intra-tumor stroma offers more information than previously fathomed. Many pathologists may recognize the phenomenon of stroma infiltrating the primary tumor. However that this parameter is of prognostic and predictive value was previously unknown, but recently published by De Kruijf et al (February 2011). (1)

Beck et al now report on an unexpected finding on the morphological interpretation of histologic sections using features analyzed by an image analysis protocol. They observed that stroma and not the tumor itself a prognostic determinant for breast cancer.

The association of the presence of cancer-stroma formation and patient outcome, has drawn interest in the clinic. The amount of intra- tumor stroma was found by initially by our group as a reproducible and simple prognostic parameter pointing towards differences in biology. The parameter can be determined on histological resection material as well as on biopsy tissue. It is remarkable that a simple cell based (retro- research) parameter using conventional microscopy can give such good predictions. This parameter was found to be a prognostic factor for colorectal cancer, esophageal and breast cancer. (2,3,4,5)

Tumor associated stroma and cancer-associated fibroblasts may play an important role in tumor progression phases.(6) It is suggested that stroma in the vicinity of tumors undergoes, or may be affected by, changes during tumor progression. The recent study of our group further supports this hypothesis.

In a cohort of 574 early breast cancer patients, stroma-high tumors had a shorter relapse free period (RFP) (p<0.001) compared to stroma- low tumors. Tumor-stroma ratio was an independent prognostic parameter (p<0.001) and also in stratified analysis based on systemic treatment. Importantly, within the triple negative cancer subpopulation patients with stroma-high tumors had a 3.19 times higher risk of relapse (p=0.003. Five year RFP-rates for triple negative cancer patients with stroma-high compared to stroma-low tumors were 46% and 81% respectively.

In conclusion, tumor-stroma ratio has shown to be a prognostic parameter in breast cancer patients, independently of other clinico- pathological parameters and systemic therapy. The tumor-stroma ratio is easy to determine, reproducible and fast performed for all breast cancers. It is a strong candidate parameter that could easily be implemented in routine daily diagnostics, to optimize risk -stratification for breast cancer patients. (1)

High intra-observer agreement Kappa values for tumor-stroma ratio were found in the studies on breast cancer, colorectal cancer as well as for esophageal cancer (between 0.85 and 0.89). This convincingly demonstrates that tumor-stroma ratio on simple routine paraffin H&E stained histological sections is a highly reproducible method. (1-5)

Literature. 1. Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients. de Kruijf EM, van Nes JG, van de Velde CJ, Putter H, Smit VT, Liefers GJ, Kuppen PJ, Tollenaar RA, Mesker WE. Breast Cancer Res Treat. 2011 Feb;125(3):687-96. 2. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Mesker WE, Junggeburt JM, Szuhai K, de Heer P, Morreau H, Tanke HJ, Tollenaar RA. Cell Oncol. 2007;29(5):387-98. 3. Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Mesker WE, Liefers GJ, Junggeburt JM, van Pelt GW, Alberici P, Kuppen PJ, Miranda NF, van Leeuwen KA, Morreau H, Szuhai K, Tollenaar RA, Tanke HJ. 4. The stromal part of adenocarcinomas of the oesophagus: does it conceal targets for therapy? Courrech Staal EF, Wouters MW, van Sandick JW, Takkenberg MM, Smit VT, Junggeburt JM, Spitzer-Naaykens JM, Karsten T, Hartgrink HH, Mesker WE, Tollenaar RA. 5. Reproducibility and validation of tumour stroma ratio scoring on oesophageal adenocarcinoma biopsies. Courrech Staal EF, Smit VT, van Velthuysen ML, Spitzer-Naaykens JM, Wouters MW, Mesker WE, Tollenaar RA, van Sandick JW. Eur J Cancer. 2011 Feb;47(3):375-82. Epub 2010 Oct 29. 6. Fibroblasts in cancer. Kalluri R, Zeisberg M. Nat Rev Cancer. 2006 May;6(5):392-401. Review.