Stromal marker predicting radiotherapy benefit in DCIS

Predictive biomarkers are urgently needed to support the individualization of radiotherapy for DCIS. Most efforts have focused on tumor cell features rather than the associated stroma. Our recent study by Strell et al. published in Clinical Cancer Research1 suggests that high expression of the stroma cell marker platelet-derived growth factor receptor beta (PDGFRb) can identify DCIS patients, who do not benefit from adjuvant radiotherapy.

CArInA STrEll, PhD, is Associate Professor in Experimental Pathology in the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden. Her field of work includes tumor stroma interactions driving the evolution and development of radiotherapy resistance in early breast cancer. ArnE ÖSTmAn, PhD, is Professor of Molecular Oncology in the Department of Oncology and Pathology at Karolinska Institutet, Stockholm, Sweden. His field of work is translational studies on the tumor microenvironment with special emphasis on cancer-associated fibroblasts.

Ductal carcinoma in situ (DCIS), a precursor of invasive breast cancer, represents about 25% of all breast cancers detected by screening in Europe. Although the prognosis is generally good, 10-20% of patients suffer a recurrence within ten years of diagnosis.2 The standard treatment for DCIS patients today comprises breast-conserving surgery followed by adjuvant whole-breast radiotherapy.

However, DCIS is a heterogeneous disease with unclear natural history, and it is recognized that the benefits of radiotherapy are highly individual. Owing to this uncertainty, the present treatment recommendations involve a high risk of overtreatment for some, and potentially many, women. Consequently, there is an urgent need to find predictive markers that can be used to avoid unnecessary or ineffective radiotherapy for DCIS patients.

Most previous studies have focused mainly on markers in the tumor cells themselves, but recent findings show that cells of the tumor microenvironment can also affect both the aggressiveness and therapeutic effects in DCIS cases. In particular cancer-associated fibroblasts have been demonstrated to influence the efficacy of radiotherapy in different cell and mouse models.3–6

PDGFRb as predictive biomarker

In our study, we retrospectively analyzed a large tissue collection from a Swedish randomized radiotherapy trial in order to investigate whether the stroma cell marker PDGFRb has any prognostic relevance or could predict the response to adjuvant radiotherapy in DCIS.

The study included 590 patients with primary DCIS who had undergone breast conserving surgery. The median follow-up time was 17.4

years. Immunohistochemical staining of PDGFRb expression was assessed by two independent raters scoring ten high-power fields within the DCIS-associated stroma.

To test the prognostic impact of stromal PDGFRb expression, analyses were restricted to the patient group not receiving radiotherapy. No significant differences in ipsilateral recurrence rates, our primary endpoint, were noted between patients with low (below median score) and high (above median score) levels of PDGFRb. Likewise, no differences were noted for distance metastasis, breast cancer specific death or overall survival, as secondary endpoints.

Notably, our data next showed that low levels of PDGFRb were associated with a prominent radiotherapeutic efficacy regarding ipsilateral recurrence for women with DCIS at 10 years after surgery (absolute risk reduction of 21%; p<0.001), while no significant benefit from radiotherapy was noted for women with high PDGFRb levels. The statistical interaction between PDGFRb and radiotherapy benefit was significant after adjustment for confounding factors including age, lesion size, nuclear grade, KI67, endocrine treatment and screen/clinical detection (pinteraction=0.008). No significant interactions were noted for the secondary endpoints.

Future tasks and directions towards clinical implementation

Our findings suggest that stromal PDGFRb is a radiotherapy predictive marker rather than a prognostic marker. However, validation in independent DCIS cohorts is an important task for planned future studies, which will be performed in collaboration with a US-based breast cancer diagnostic company. Validation studies should also include comparisons with other DCIS risk assessment approaches, which predict the recurrence risk for individual patients in order to guide treatment decisions such as the OncotypeDx DCIS score (Exact Sciences).

From a tumor biology point of view, it is still unclear whether in this situation PDGFRb acts as marker of a fibroblast subset modulating the radiosensitivity of DCIS cells, or whether it is a key active signaling player in this process. Therefore, future efforts should also address the biological mechanisms behind our finding. PDGFRb is a key regulator of fibroblasts and pericytes and its role has been well documented in the context of developmental as well as tumor biology studies. Our previous work on DCIS has also indicated that high PDGFRb expression in fibroblasts is associated with a high production of TGF-beta ligands,7 a key modulator of radiosensitivity in tumor cells.6

Nevertheless, further experimental studies using in vivo models specifically for the adjuvant radiotherapy setting are needed in order to decipher the role of stromal PDGFRb-signaling in the radiosensitivity of DCIS. Specific PDGFRb targeting drugs such as PDGFRb affibodies (Affibody AB) have recently been developed, and these would represent ideal candidates for inclusion in upcoming experimental studies. Ultimately, we believe that findings from such studies could eventually pave the way for novel radiosensitizing combination therapies with a PDGFRb targeting component.

Conclusion

Our study identifies PDGFRb as a possible radiotherapy predictive marker in DCIS. Validation studies and experimental approaches to decipher the underlying biology are our future priorities. Together, those efforts offer the potential to develop PDGFRb towards a novel, clinically-relevant biomarker and to identify new combinatorial treatment strategies.

References:

1.Strell C, Folkvaljon D, Holmberg E, et al. High PDGFRb Expression Predicts Resistance to Radiotherapy in DCIS within the SweDCIS Randomized Trial. Clin Cancer Res. 2021 Jun 15;27(12): 3469-3477. DOI:10.1158/1078-0432.CCR-20-4300. 2 Wärnberg F, Garmo H, Emdin S, et al. Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS. Trial. J Clin Oncol. 2014 Nov 10;32(32): 3613-3168. DOI:10.1200/JCO.2014.56.2595. 3 Sizemore GM, Balakrishnan S, Thies KA, et al. Stromal PTEN determines mammary epithelial response to radiotherapy. Nature Communications. 2018 Jul 17;9(1): 2783. DOI:10.1038/s41467-018-05266-6. 4 Mantoni TS, Lunardi S, Al-Assar O, Masamune A, Brunner TB. Pancreatic stellate cells radioprotect pancreatic cancer cells through β1-integrin signaling. Cancer Res. 2011 May 15;71(10): 3453-3458. DOI:10.1158/0008-5472.CAN-10-1633. 5 Park CC, Zhang HJ, Yao ES, Park CJ, Bissell MJ. Beta1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res. 2008 Jun 1;68(11): 4398-4405. DOI:10.1158/0008-5472.CAN-07-6390. 6 Krisnawan VE, Stanley JA, Schwarz JK, DeNardo DG. Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance. Cancers. 2020 Oct 11;12(10): 2916. DOI:10.3390/cancers12102916. 7 Strell C, Paulsson J, Jin S-B, et al. Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ. J Natl Cancer Inst. 2019 Sep 1;111(9): 983-995. DOI:10.1093/jnci/djy234.