Examination of Tumor Regression Grading Systems in Breast Cancer Patients Who Received Neoadjuvant Therapy

Primary systemic or neoadjuvant chemotherapy of breast cancer has become a standard therapy option in locally advanced or predefined intrinsic subtypes such as triple negative or Her2 positive breast cancer. Neoadjuvant chemotherapy can result in complete pathological response without residual tumor cells (tumor bed) or partial response and non-response with different amounts of reactive stroma and residual tumor cells. The interaction between therapy regimens and tumoral driver mutations have been extensively studied, although the reactive stroma of the tumor bed received less attention. In this study, we characterized the mutational status of residual breast cancer cells and reactive tumor stroma devoid of residual tumor cells in partial or non-responders using next generation sequencing. Twenty-one post-therapeutic breast surgical specimens after neoadjuvant chemotherapy underwent pathogenic driver-mutation screening using microdissected residual breast cancer cells and in reactive stroma adjacent to tumor bed areas. In reactive stroma, no mutations could be validated. In residual breast cancer cells, mutations were detected in sixteen of twenty-one cases (76%). In nine of these twenty-one cases (43%), pathogenic driver mutations (PIK3CA, PTEN, TP53, FN1, PLAG1) were identified. Pathogenic driver-mutations are exclusively restricted to residual carcinoma cells and are absent in reactive stroma independently from intrinsic breast cancer subtypes or tumor stage. These data suggest that the absence of pathogenic mutations in a tumor bed without residual tumor cells may have prognostic implications after neoadjuvant chemotherapy.

Section: Methodsmentioning

confidence: 99%

Next Generation Sequencing of Reactive Stroma and Residual Breast Cancer Cells in Tumor Bed after Neoadjuvant Chemotherapy

Varga

Christiansen

Lukamowicz-Rajska

et al. 2022

“…Among the neoadjuvant cases, the therapeutic response to therapy was evaluated in the surgical specimen according to the Denkert tumor regression grade (TRG) system as follows: 0 = no effect, 1 = resorption and tumor sclerosis, 2 = minimal residual invasive tumor (<5 mm), 3 = residual noninvasive tumor only, 4 = no tumor detectable [ 16 ], and pathological complete response (pCR) if no invasive cancer tissue was found in either the breast tissue or the lymph nodes. Later on, the dates of eventual relapses were registered.…”

Section: Methodsmentioning

confidence: 99%

BC-Monitor: Towards a Routinely Accessible Circulating Tumor DNA-Based Tool for Real-Time Monitoring Breast Cancer Progression and Treatment Effectiveness

Priskin¹,

Pólya²,

Pintér³

et al. 2021

Self Cite

Circulating tumor DNA (ctDNA) is increasingly employed in the screening, follow-up, and monitoring of the continuously evolving tumor; however, most ctDNA assays validated for clinical use cannot maintain the right balance between sensitivity, coverage, sample requirements, time, and cost. Here, we report our BC-monitor, a simple, well-balanced ctDNA diagnostic approach using a gene panel significant in breast cancer and an optimized multiplex PCR-based NGS protocol capable of identifying allele variant frequencies below 1% in cell-free plasma DNA. We monitored a cohort of 45 breast cancer patients prospectively enrolled into our study receiving neoadjuvant chemotherapy or endocrine therapy or palliative therapy for metastatic diseases. Their tumor mutation status was examined in the archived tumor samples and plasma samples collected before and continuously during therapy. Traceable mutations of the used 38-plex NGS assay were found in approximately two-thirds of the patients. Importantly, we detected new pathogenic variants in follow-up plasma samples that were not detected in the primary tumor and baseline plasma samples. We proved that the BC-monitor can pre-indicate disease progression four–six months earlier than conventional methods. Our study highlights the need for well-designed ctDNA monitoring during treatment and follow-up, integrated into a real-time treatment assessment, which could provide information on the active tumor DNA released into the blood.

“…Indeed, NAC can induce numerous tissue changes and even the identification of the primary tumor bed can be challenging because it resembles to fibrotic breast tissue. It is therefore crucial to localize the tumor before starting neoadjuvant treatment (e.g., by clips) [ 58 ]. In their evaluation, pathologists report the size of the primary tumor bed in three dimensions and the size and number of any residual neoplastic foci, along with the distance of the tumor bed/residual tumor from the surgical margins in the case of breast-conserving surgery [ 55 , 59 ].…”

Section: Pathological Evaluation Of Residual Diseasementioning

confidence: 99%

“…RCB is associated with survival outcomes, especially in more aggressive BC subtypes, namely TNBC and HER2+ [ 62 ]. RCB is the most used grading scores in the United States and in many other countries [ 58 ]. RCB assessments depend on tumor bed size, tumor cellularity, number of positive lymph nodes, and size of the largest lymph node metastasis.…”

Section: Pathological Evaluation Of Residual Diseasementioning

confidence: 99%

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

Agostinetto

Jacobs

Debien

et al. 2022

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be “salvaged” through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies.