Jérôme Lacombe

Proteomic approaches to identify biomarkers predictive of radiotherapy outcomes

To be highly successful, a radiotherapeutic dose must be sufficiently large to destroy radioresistant tumors, yet avoid injuring the surrounding healthy tissue. However, many patients exhibit high radiosensitivity and may develop radiation-induced early and late side effects. Because the identification of these radiosensitive patients remains largely problematic, general radiotherapy protocols currently limit the dose given, which risks delivering an insufficient dose to a significant number of less sensitive patients. Therefore, one of the main current challenges of radiobiology is to predict a patient’s tumor radioresistance and normal tissue radiosensitivity to tailor a personalized treatment to that individual. Although predictive assays exist, none has demonstrated highly significant results that would be useful in a clinical setting. Therefore, proteomics represents a promising approach for identifying new relevant predictive biomarkers. In this review, the authors first explain the main characteristics of tumor radioresistance and normal tissue radiosensitivity. The authors next describe the existing predictive assays. Finally, the proteomics studies performed to date to identify new biomarkers that probably predicts radiotherapy outcomes are discussed.

Serum Autoantibody Signature of Ductal Carcinoma In Situ Progression to Invasive Breast Cancer

Purpose: The identification of markers associated with progression to invasive breast cancer (IBC) is a major factor that can guide physicians in the initial therapeutic decision and the management of ductal carcinoma in situ (DCIS). Experimental Design: We examined autoantibody targets in 20 DCIS and 20 IBC patients using protein microarrays and identified humoral responses that can be used to distinguish the two groups. The five most differentially targeted antigens were selected to generate an autoantibody signature for the in situ to invasive breast cancer transition. This signature was next tested on 120 independent samples (61 DCIS and 59 IBC) using specific ELISA assays. The prognosis value of the autoantibody signature was finally evaluated in a cohort of DCIS patients followed for 5 years. Results: A set of five autoantibody targets (RBP-Jκ, HMGN1, PSRC1, CIRBP, and ECHDC1) with the highest differential signal intensity found in the protein microarrays experiment was used to establish an autoantibody signature of the DCIS to IBC transition. Using ELISA, this signature significantly discriminated DCIS from IBC [area under the ROC curve (AUC) = 0.794, 95% confidence interval (CI): 0.674–0.877]. Interestingly, our panel could highly distinguish low-grade DCIS from high-grade DCIS exhibiting an AUC of 0.749 (95% CI: 0.581–0.866). Finally, using a Kaplan–Meier analysis, the autoantibody signature could significantly divide the DCIS patients into a poor prognosis group and a good prognosis group (P = 0.01). Conclusion: These results indicate the potential of autoantibody detection as a new prognostic test with possible clinical implications for the management of DCIS. Clin Cancer Res; 18(7); 1992–2000. ©2012 AACR.

Use of autoantibodies to detect the onset of breast cancer.

The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, particularly for in situ carcinoma and early-stage breast cancer. However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures. Although magnetic resonance imaging is a highly sensitive detection tool that has become standard for women at very high risk of developing breast cancer, it lacks sufficient specificity and costeffectiveness for use as a general screening tool. Therefore, there is an important need to improve screening and diagnosis of early-invasive and noninvasive tumors, that is, in situ carcinoma. The great potential for molecular tools to improve breast cancer outcomes based on early diagnosis has driven the search for diagnostic biomarkers. Identification of tumor-specific markers capable of eliciting an immune response in the early stages of tumor development seems to provide an effective approach for early diagnosis. The aim of this review is to describe several autoantibodies identified during breast cancer diagnosis. We will focus on these molecules highlighted in the past two years and discuss the potential future use of autoantibodies as biomarkers of early-stage breast cancer.

Identification and validation of new autoantibodies for the diagnosis of DCIS and node negative early‐stage breast cancers

Evidence of circulating autoantibodies in cancer patient sera has created opportunities for exploiting them as biomarkers. We report the identification and the clinical validation of an autoantibody panel in newly diagnosed patients with early‐stage breast cancer. Proteomic approach and serological screening of a discovery set of sera (n = 80) were performed to identify tumor‐associated antigens (TAAs). Autoantibody levels were then measured in an independent validation set (n = 182) against a panel of five TAAs by enzyme‐linked immunosorbent assay. Sixty‐seven antigens that elicited a specific humoral response in breast cancer were identified and five antigens (GAL3, PAK2, PHB2, RACK1 and RUVBL1) were selected for validation. GAL3 and RACK1 showed significantly increased reactivity in early‐stage breast cancer. When combined, the five markers significantly discriminated early‐stage cancer from healthy individuals (AUC = 0.81; 95% CI [0.74–0.86]). Interestingly, this value was high in both node‐negative early‐stage primary breast cancer (AUC = 0.81; 95% CI [0.72–0.88]) and ductal carcinoma in situ (AUC = 0.85; 95% CI [0.76–0.95]) populations. This autoantibody panel could be useful as a diagnostic tool in a screening strategy of early‐stage invasive breast cancer and preinvasive breast cancer. It could be particularly appropriate in complement to mammography for women with high breast density.

A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women

Background: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging. Methods: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2). Circulating autoantibody levels were measured in a cohort of 396 serum samples from histologically confirmed DCIS (n = 87) or T1N0 PBC (n = 153) and healthy controls (n = 156). Results: Individually, antibodies against CCNB1, FKBP52, GAL3, PAK2, PRDX2, PPIA, P53, and MUC1 demonstrated discriminatory power between breast cancer and healthy control groups. At 90% sensitivity, the overall combined specificity of the autoantibody serum screening test was 42%. Adjustment for higher sensitivities of 95% and 99% resulted in 30% and 21% specificities, respectively (33% and 18% in T1N0 PBC and 28% and 21% in DCIS). Finally, in patients with node-negative early-stage breast cancer younger than 50 years, the autoantibody assay exhibited 59% specificity with a fixed sensitivity at 90%. Conclusions: Our autoantibody panel allows accurate detection of early breast cancer and DCIS, notably in younger patients. Impact: Clinical assessment of this autoantibody panel displays a potential to facilitate clinical management of early-stage breast cancer detection in cases of inconclusive mammogram. Cancer Epidemiol Biomarkers Prev; 23(9); 1834–42. ©2014 AACR.

Radiosensibilité individuelle : les tests vont changer nos pratiques

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. In a same population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists, namely in terms of late side effects that are in principle non-reversible. This review details the different radiobiological approaches that have been developed to better understand the mechanisms of radiation-induced late effects. We also present the possibilities of clinical use of predictive assays in the close future.

Intérêt des marqueurs sanguins dans la prédiction de la toxicité radio-induite

The oncologic outcome and the total dose are highly correlated with the treatment by ionizing radiation. The dose increase (total or per fraction) may provoke late-side effects that are potentially irreversible. The radiation-induced CD8 lymphocyte apoptotic value and the molecular modifications within the lymphocyte are capable of predicting the level of risk of developing late-side effects after curative intent radiotherapy. In this review, we present the different blood assays in this setting and discuss the current possibilities of researches, namely those involving the proteomic process.

Les tests de radiosensibilité des tissus sainsRadiosensitivity assays of normal tissues

Radiotherapy allows locoregional control with systemic impact in some indications. Technologic advances decrease the dose received by normal tissues leading to a low crude number of late side effects near to 5%. Intrinsic radiosensitivity are still of interest in this context of high level of technology and optimized treatments. Assays of radiosensitivity are detailed in this article arguing the negative results but also the perspectives.

Les tests de radiosensibilité des tissus sains

Radiotherapy allows locoregional control with systemic impact in some indications. Technologic advances decrease the dose received by normal tissues leading to a low crude number of late side effects near to 5%. Intrinsic radiosensitivity are still of interest in this context of high level of technology and optimized treatments. Assays of radiosensitivity are detailed in this article arguing the negative results but also the perspectives.