Evaluation of PD-L1 and tumor infiltrating lymphocytes in paired pretreatment biopsies and post neoadjuvant chemotherapy surgical specimens of breast carcinoma

Herein it was evaluated the impact of PD-L1 immunohistochemical expression and stromal tumor-infiltrating lymphocyte (sTIL) counts in pretreatment needle core biopsy on response to neoadjuvant chemotherapy (NACT) for patients with breast carcinomas (BC). In 127 paired pre- and post-NACT BC specimens, immunohistochemical expression of PD-L1 was evaluated in stroma and in neoplastic cells. In the same samples sTILs were semi-quantified in tumor stroma. Post-NACT specimens were histologically rated as having residual cancer burden (RCB of any degree), or with complete pathological response (pCR). PD-L1 expression and higher sTIL counts were associated with histological grade 3 BC. PD-L1 expression was also associated with the non-luminal-HER2+ and triple negative immunohistochemical profiles of BC. Pathological complete response was associated with histological grade 3 tumors, and with the non-luminal-HER2+ and triple negative profiles. Additionally, our results support an association between PD-L1 expression and pCR to NACT. It was also observed that there is a trend to reduction of sTIL counts in the post-NACT specimens of patients with pCR. Of note, PD-L1 was expressed in half of the hormone receptor positive cases, a finding that might expand the potential use of immune checkpoint inhibitors for BC patients.

Validation of the Residual Cancer Burden Index as a prognostic tool in women with locally advanced breast cancer treated with neoadjuvant chemotherapy

AimsTo correlate the ‘Residual Cancer Burden’ (RCB) index with overall survival (OS) and disease-free survival (DFS) in women undergoing neoadjuvant chemotherapy at the Cancer Institute of the State of São Paulo.MethodsWe analysed the medical records of patients with breast cancer who underwent neoadjuvant chemotherapy and breast surgery, from 2011 to December 2017. Variables analysed were age, clinical and pathological staging, molecular subtype, number of recurrences or metastases, number of deaths, value and class of the RCB index. We used the Kaplan-Meier and the log-rank statistics to evaluate the possible association between RCB and OS and DFS. A regression model was used to determine the independent association of the RCB with the outcomes controlling for confounding factors.Results347 patients were included in the analysis with a mean age of 49.39 years. Initial clinical staging was T3 in 57.9% of patients and 43.8% of patients had N1 axillary status. Survival analysis showed a statistically significant better prognosis for the RCB 0 (pCR) subgroup compared with RCB 1, 2 and 3 (log rank p=0.01). In a multivariate analysis, only the RCB classification showed a statistically significant correlation with DFS (RCB 1, HR 6.9, CI 1.9 to 25.4, p=0.004; RCB 2, HR 4.2, CI 1.6 to 10.8, p=0.03; and RCB 3, HR 7.6, CI 2.76 to 20.8, p=0.00).ConclusionWe demonstrated a positive and significant relationship between the RCB index and the risk of relapse and death.

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2− Breast Cancer: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Cyclin-dependent kinase (CDK) 4/6 inhibitors have been advocated for adjuvant therapy of metastatic hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)− breast cancer (BC). However, the efficiency of adding CDK 4/6 inhibitors to neoadjuvant therapy was not unequivocal. <b><i>Objective:</i></b> The aim of the study was to evaluate the efficiency and toxicity of neoadjuvant CDK 4/6 inhibitors + endocrine therapy (ET) versus neoadjuvant endocrine monotherapy or standard neoadjuvant chemotherapy in HR+/HER2− BC. <b><i>Method:</i></b> We searched PubMed, the Cochrane Library, Web of Science, and Embase online databases for randomized controlled trials and single-arm studies written in English until April 2021. <b><i>Results:</i></b> Five studies comparing CDK 4/6 inhibitors + ET as neoadjuvant treatments to ET alone and 2 studies comparing neoadjuvant CDK 4/6 inhibitors + ET to neoadjuvant chemotherapy were analysed. Neoadjuvant CDK 4/6 inhibitors + ET improved the rate of complete cell cycle arrest (CCCA: central Ki67 &#x3c; 2.7%, odds ratio [OR] = 7.91, 95% confidence interval [CI] = 4.81–13.03, <i>p</i> &#x3c; 0.001), increased the risk of adverse events (AEs; especially ≥3 AEs; AEs of all grades: OR = 9.10, 95% CI = 2.39–34.58, <i>p</i> = 0.001; AEs ≥3: OR = 12.24, 95% CI = 4.17–35.88, <i>p</i> &#x3c; 0.001), led to no significant differences in pathological complete response (pCR) in patients with BC (OR = 0.34, 95% CI = 0.04–2.85, <i>p</i> = 0.318) compared to endocrine monotherapy. Moreover, subgroup analysis showed that the 3 types of CDK 4/6 inhibitors all improved the rate of CCCA (ribociclib: OR = 10.31, 95% CI = 3.59–29.61, <i>p</i> &#x3c; 0.001; palbociclib: OR = 7.39, 95% CI = 1.26–43.40, <i>p</i> = 0.027, and abemaciclib: OR = 8.28, 95% CI = 3.41–20.11, <i>p</i> &#x3c; 0.001). Compared to neoadjuvant chemotherapy, neoadjuvant CDK 4/6 inhibitors plus ET decreased the risk of AEs ≥3 (OR = 0.50, 95% CI = 0.29–0.87, <i>p</i> = 0.015) and showed similar ability to reach pCR (OR = 0.50, 95% CI = 0.12–2.07, <i>p</i> = 0.342) and reduce the residual cancer burden (RCB, RCB 0–1: OR = 0.47, 95% CI = 0.18–1.22, <i>p</i> = 0.121; RCB 2–3: OR = 2.30, 95% CI = 0.89–5.91, <i>p</i> = 0.084). <b><i>Conclusions:</i></b> The results suggested that combination therapy had increased efficacy and toxicity compared to endocrine monotherapy and showed similar efficacy to and better safety than neoadjuvant chemotherapy.

Radiological and pathological assessment of response to neoadjuvant CDK4/6 inhibitor and endocrine treatments in a real-life setting—initial results

Background Neoadjuvant endocrine therapy is an alternative to neoadjuvant chemotherapy in women with inoperable luminal-like breast cancers. Neoadjuvant cyclin-dependent kinase 4/6 inhibitor treatment combined with endocrine treatment (CDK4/6I + E) is interesting given the combination’s utility in the treatment of metastatic breast cancer. Currently, the literature on the radiological response evaluation of patients treated with neoadjuvant CDK4/6I + E in a real-life setting is scarce. Purpose To conduct a radiological response evaluation of patients treated with neoadjuvant CDK4/6I + E in a real-life setting. Material and methods We retrospectively reviewed clinical, pathological, and radiological findings of six patients with luminal-like breast cancers treated with neoadjuvant CDK4/6I + E treatment. The radiological neoadjuvant CDK4/6I + E response was evaluated with the RECIST 1.1 criteria and the pathological residual disease was assessed using the Residual Cancer Burden (RBC) criteria. Results None of the patients achieved a complete radiological magnetic resonance imaging (MRI)–determined response or a complete pathological response; three (50%) patients had a partial radiological response; in the three others, the disease remained stable radiologically. All of the tumors were rendered susceptible to surgical treatment. Two out of six (33.3%) patients had a moderate response (RBC-II); four (66.7%) had an extensive residual disease (RBC-III) in the final surgical sample. Conclusion Although none of the patients achieved a pathologically complete response, neoadjuvant CDK4/6I + E treatment rendered all tumors operable. MRI appears to be reliable in the assessment of the neoadjuvant CDK4/6I + E treatment response in a real-life setting. Larger studies are warranted to confirm these results.

HER2 Testing Characteristics Can Predict Residual Cancer Burden following Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer

Objectives. The response to HER2-targeted neoadjuvant chemotherapy (NAC) in HER2-positive (+) breast cancer can be quantified using residual cancer burden (RCB) pathologic evaluation to predict relapse free/overall survival. However, more information is needed to characterize the relationship between patterns of HER2 testing results and response to NAC. We evaluated clinicopathologic characteristics associated with RCB categories in HER2+ patients who underwent HER2-directed NAC. Methods. A retrospective chart review was conducted with Stage I–III HER2+ breast cancer cases following NAC and surgical resection. HER2 immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH), histologic/clinical characteristics, hormone receptor status, and RCB scores (RCB-0, RCB-I, RCB-II, and RCB-III) were evaluated. Results. 64/151 (42.4%) patients with HER2+ disease had pathologic complete response (pCR). Tumors with suboptimal response (RCB-II and RCB-III) were more likely to demonstrate less than 100% HER2 IHC 3+ staining ( p < 0.0001 ), lower HER2 FISH copies ( p < 0.0001 ), and lower HER2/CEP17 ratios ( p = 0.0015 ) compared to RCB-I and RCB-II responses. Estrogen receptor classification using ≥10% versus ≥1% staining showed greater association with higher RCB categories. Conclusions. HER2+ characteristics show differing response to therapy despite all being categorized as positive; tumors with less than 100% IHC 3+ staining, lower HER2 FISH copies, and lower HER2/CEP17 ratios resulted in higher RCB scores.

Evaluation of intra-tumoral (IT) SD-101 and pembrolizumab (Pb) in combination with paclitaxel (P) followed by AC in high-risk HER2-negative (HER2-) stage II/III breast cancer: Results from the I-SPY 2 trial.

508 Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (>85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379. [Table: see text]

Treatment Efficacy Score (TES), a continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between trial arms in the I-SPY 2 trial.

587 Background: Residual cancer burden (RCB) is a continuous score that captures the amount of residual cancer after neoadjuvant chemotherapy and predicts disease recurrence and survival across all breast cancer subtypes. RCB score 0 corresponds to pathological complete response (pCR; ypT0, ypN0). We hypothesize that comparison of the distributions of RCB scores between randomized treatment arms of a trial could predict treatment effect on recurrence free survival better than comparison of pCR rates only. Methods: The cancer Treatment Efficacy Score (TES) compares efficacies of two treatments using non-continuous RCB results. We examined (i) area between cumulative distribution (ABC) functions; (ii) density ratio of RCB scores; and (iii) density difference of RCB scores from two treatments, to select the most efficient metric to compute TES. A random permutation procedure was used to estimate the p-value from each test. These methods were applied to data from the durvalumab/olaparib arm and corresponding controls of the I-SPY2 trial, separately by molecular subtype. In subsampling and simulation experiments we assessed robustness of results including power and false positive rate control under variable sample sizes to select the most robust TES metric. The other 11 experimental arms of I-SPY2 were used to assess the performance of the final metric. We calculated correlation between TES and (i) pCR rate difference, and 3- and 5-year (ii) event-free (EFS) and (iii) distant recurrence free survivals (DRFS). Results: RCB scores are multimodal and do not follow normal distribution.In simulated data ABC provided more stable results than the other methods, had good power, performed well with small sample sizes, resulted in low false positive rate, required the least computational time, and therfore was selected as the TES metric for validation in 11 arms of I-SPY2. We found a high correlation between difference in pCR rate and TES value across all molecular subtypes in each of the 11 trial arms (r = 0.92, p = 1.7e-8). There was also significant linear relationship between TES and survival estimates in EFS (r = 0.58, p = 9.3e-3 for 3-years survival; r = 0.62, p = 4.8e-3 for 5-years survival) and DRFS (r = 0.56, p = 1.2e-2 for 3-years survival; r = 0.54, p = 1.8e-2 for 5-years survival). Statistically significant TES score correlated significantly with higher benefit in 3-years survival (p = 9.7e-4 for EFS; p = 5.7e-3 for DRFS) and 5-years survival (p = 9.7e-4 for EFS; p = 3.0e-3 for DRFS). In most instances, this correlation with survival was higher than seen with pCR difference. Conclusions: TES is a novel more optimal metric to identify the more effective cytotoxic neoadjuvant regimen from the entire distribution of pathologic response that significantly correlates with event and recurrence free survival and may serve as a better surrogate than pCR rate difference.