Clinical Tumor Response Research Articles

Raman spectroscopy and convolutional neural networks for monitoring biochemical radiation response in breast tumour xenografts

Tumour cells exhibit altered metabolic pathways that lead to radiation resistance and disease progression. Raman spectroscopy (RS) is a label-free optical modality that can monitor post-irradiation biomolecular signatures in tumour cells and tissues. Convolutional Neural Networks (CNN) perform automated feature extraction directly from data, with classification accuracy exceeding that of traditional machine learning, in cases where data is abundant and feature extraction is challenging. We are interested in developing a CNN-based predictive model to characterize clinical tumour response to radiation therapy based on their degree of radiosensitivity or radioresistance. In this work, a CNN architecture is built for identifying post-irradiation spectral changes in Raman spectra of tumour tissue. The model was trained to classify irradiated versus non-irradiated tissue using Raman spectra of breast tumour xenografts. The CNN effectively classified the tissue spectra, with accuracies exceeding 92.1% for data collected 3 days post-irradiation, and 85.0% at day 1 post-irradiation. Furthermore, the CNN was evaluated using a leave-one-out- (mouse, section or Raman map) validation approach to investigate its generalization to new test subjects. The CNN retained good predictive accuracy (average accuracies 83.7%, 91.4%, and 92.7%, respectively) when little to no information for a specific subject was given during training. Finally, the classification performance of the CNN was compared to that of a previously developed model based on group and basis restricted non-negative matrix factorization and random forest (GBR-NMF-RF) classification. We found that CNN yielded higher classification accuracy, sensitivity, and specificity in mice assessed 3 days post-irradiation, as compared with the GBR-NMF-RF approach. Overall, the CNN can detect biochemical spectral changes in tumour tissue at an early time point following irradiation, without the need for previous manual feature extraction. This study lays the foundation for developing a predictive framework for patient radiation response monitoring.

Feasibility of Intratumoral Anti-PD1 as Treatment of Human Basal Cell Carcinoma: An Explorative Study with Adjuvant Ablative Fractional Laser

The use of immune checkpoint inhibitors (ICI) is expanding with the approval for advanced/metastatic keratinocyte carcinoma; however, most tumors are non-aggressive. Local administration could broaden ICI, but adequate immune response might require an immune-attractive adjuvant such as ablative fractional laser (AFL). Accordingly, this study aimed to explore intratumoral injection of anti-PD1 with and without AFL in basal cell carcinoma (BCC), exploring anti-PD1 concentration, immune cell infiltration, tumor response, and safety. This open-label, proof-of-concept trial investigated intratumoral anti-PD1 + AFL combination therapy versus anti-PD1 or AFL monotherapy in 28 BCC patients. The primary endpoints were immune cell infiltration evaluated immunohistochemically and clinical tumor response after 3 months. The secondary outcomes were tumoral drug concentration and safety. The most robust response was obtained following intervention with combined anti-PD1+AFL, leading to a ~2.5-fold increase in CD3+ cells (p = 0.027), and tumor reduction ≥25% in 73%, including two tumors with complete remission. Upon anti-PD1 monotherapy, a slight decrease in CD3+ cells was observed while a non-significant increase following AFL was seen. Tumor reduction ≥25% was seen in 45% and 50%, respectively, after anti-PD1 and AFL monotherapy. The CD8/CD3 ratio remained unchanged after anti-PD1+AFL and anti-PD1 monotherapy, while AFL led to a decreased ratio. A non-significant decline in the Foxp3/CD3 ratio was observed for all groups. Side-effects were mild with no systemic drug concentration detected. Intratumoral anti-PD1 injection is feasible, and a single exposure to locally injected anti-PD1 with adjuvant AFL increased immune cell infiltration and reduction in BCC with limited side-effects.

Differences and Similarities in the Pattern of Early Metabolic and Morphologic Response after Induction Chemo-Immunotherapy versus Induction Chemotherapy Alone in Locally Advanced Squamous Cell Head and Neck Cancer.

Simple SummaryThere are differences and similarities when assessing the short-term therapeutic response of chemotherapy and chemotherapy plus immunotherapy using imaging techniques, which may be necessary to make treatment decisions in malignant head and neck tumors. After both chemo- and immunochemotherapy, remission becomes measurable in cross-sectional and metabolic diagnostics after only one cycle of therapy, with 18FDG-PET/CT predicting complete remission of tumor cells in a representative biopsy better than MRI/CT examination in both therapeutic modalities. While complete tumor remission is highly likely (88%) after immunochemotherapy in tumors with low residual activity (≤40% of initial SUV), this is less common after chemotherapy alone (65%). In metabolic nonresponse with more than 80% residual activity, the probability of complete remission nevertheless is low after chemotherapy alone (6%). After immunochemotherapy, these false nonresponders are common (35%), requiring additional diagnostics by deep biopsy. Cases of pseudoprogression with an increase of SUVmax of more than 125% of the baseline were not observed.Background: In head and neck cancer patients, parameters of metabolic and morphologic response of the tumor to single-cycle induction chemotherapy (IC) with docetaxel, cis- or carboplatin are used to decide the further course of treatment. This study investigated the effect of adding a double immune checkpoint blockade (DICB) of tremelimumab and durvalumab to IC on imaging parameters and their significance with regard to tumor cell remission. Methods: Response variables of 53 patients treated with IC+DICB (ICIT) were compared with those of 104 who received IC alone. Three weeks after one cycle, pathologic and, in some cases, clinical and endoscopic primary tumor responses were evaluated and correlated with a change in 18F-FDG PET and CT/MRI-based maximum-standardized uptake values (SUVmax) before (SUVmaxpre), after treatment (SUVmaxpost) and residually (resSUVmax in % of SUVmaxpre), and in maximum tumor diameter (Dmax) before (Dmaxpre) and after treatment (Dmaxpost) and residually (resD). Results: Reduction of SUVmax and Dmax occurred in both groups; values were SUVmaxpre: 14.4, SUVmaxpost: 6.6, Dmaxpre: 30 mm and Dmaxpost: 23 mm for ICIT versus SUVmaxpre: 16.5, SUVmaxpost: 6.4, Dmaxpre: 21 mm, and Dmaxpost: 16 mm for IC alone (all p < 0.05). ResSUVmax was the best predictor of complete response (IC: AUC: 0.77; ICIT: AUC: 0.76). Metabolic responders with resSUVmax ≤ 40% tended to have a higher rate of CR to ICIT (88%; n = 15/17) than to IC (65%; n = 30/46; p = 0.11). Of the metabolic nonresponders (resSUVmax > 80%), 33% (n = 5/15) achieved a clinical CR to ICIT versus 6% (n = 1/15) to IC (p = 0.01). Conclusions: ICIT and IC quickly induce a response and 18F-FDG PET is the more accurate modality for identifying complete remission. The rate of discrepant response, i.e., pCR with metabolic nonresponse after ICIT was >30%.

Organ-specific efficacy in advanced non-small cell lung cancer patients treated with first-line single-agent immune checkpoint inhibitors.

Background:Response to immune checkpoint inhibitors (ICIs) is affected by multiple factors. This study aimed to explore whether sites of metastasis are associated with clinical outcomes of ICIs in advanced non-small-cell lung cancer (NSCLC) patients.Methods:The data of NSCLC patients with high programmed death-ligand 1 expression and good performance status receiving first-line ICIs monotherapy from Guangdong Provincial People's Hospital between May 2019 and July 2020 were retrospectively analyzed. Metastatic sites included liver, bone, brain, adrenal gland, pleura, and contralateral lung. Progression-free survival (PFS) and overall survival (OS) were compared between different metastatic sites and metastatic burden by the Kaplan-Meier method. Organ-specific disease control rate (OSDCR) of different individual metastatic sites was evaluated.Results:Forty NSCLC patients meeting the criteria were identified. The presence of liver metastasis was significantly associated with shorter PFS (3.1 vs. 15.5 months, P = 0.0005) and OS (11.1 months vs. not reached, P = 0.0016). Besides, patients with bone metastasis tend to get shorter PFS (4.2 vs. 15.5 months, P = 0.0532) rather than OS (P = 0.6086). Moreover, the application of local treatment could numerically prolong PFS in patients with brain metastasis (15.5 vs. 4.3 months, P = 0.1894). More metastatic organs involved were associated with inferior PFS (P = 0.0052) but not OS (P = 0.0791). The presence of liver metastasis or bone metastasis was associated with more metastatic organs (Phi[ϕ]: 0.516, P = 0.001). The highest OSDCR was observed in lung (15/17), and the lowest in the liver (1/4).Conclusions:Metastases in different anatomical locations may be associated with different clinical outcomes and local tumor response to ICIs in NSCLC. ICIs monotherapy shows limited efficacy in patients with liver and bone metastasis, thus patients with this type of metastasis might require more aggressive combination strategies.

Circulating tumor DNA (ctDNA) in HER2 exon 20 insertion mutations and responses in NSCLC HER2 exon 20 insertion treated with poziotinib.

3051 Background: ctDNA levels in plasma samples permits temporal assessment of tumor mutational status and tumor burden during therapy. Poziotinib is an oral HER2 TKI in development for NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in HER2 exon 20 insertion mutations and other driver mutations in first- and second-line patients comparing to clinical response per RECIST1.1. Methods: NSCLC patients harboring HER2 exon 20 insertion mutations were enrolled into the poziotinib ZENITH20 using tumor tissue based NGS. Serial plasma samples were collected at baseline, at C3D1, at Day 1 of every other cycle until disease progression. The Guardant360â 74-gene liquid biopsy assay was used to assess changes in tumor-associated somatic variants including the target variant HER2 exon20 insertion as well as other emergent driver mutations in ctDNA as expressed as percent variant allele frequency (%VAF). Results: 23 first- and second-line NSCLC patients were evaluable with tumor tissue confirmation of HER2 exon 20 insertion mutations. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations (mean % VAF 20±5) resulting in a concordance of 95% versus tissue based NGS. 7 patients had serial testing through C7D1 permitting assessment of ctDNA dynamics and comparison to clinical responses. 5 of 7 (71%) serially tested patients treated with poziotinib at 16mg QD had undetectable HER2 exon 20 insertion at C3D1 which was associated with a tumor response PR. Tumor escape (PD) was observed in 2 of the 5 patients which correlated with increases in target HER2 exon 20 insertion VAF in the plasma with the remaining 3 patients ≥PR. Notably, the rise in HER2 exon 20 in ctDNA occurred prior to tumor escape. In one patient treated with poziotinib at 16 mg QD we observed undetectable levels of the HER2 exon 20 insertion in ctDNA at C3D1 which continued through C16. This patient’s responses correlated with patient tumor response of SD at C2 which then became PR through C9 and CR through C17. Conclusions: Poziotinib treatment resulted in reductions in HER2 exon 20 insertion mutations in ctDNA preceded and correlated with the clinical tumor response. Increases in ctDNA HER2 exon 20 insertion mutations were observed prior to confirmation of tumor escape. Serial monitoring of ctDNA is a potential predictive biomarker for treatment response and disease progression. Future evaluation in a larger population is required to confirm the impact of these findings.

Pazopanib in metastatic soft tissue sarcoma (STS): Results of a multi-institutional observational study.

e23542 Background: Soft tissue sarcomas (STS) are a heterogenous group of tumors which have limited therapeutic options and poor prognosis in advanced/metastatic settings. Herein, we present the clinical outcomes of metastatic STS patients treated with pazopanib (PAZ) in real-life. Methods: We retrospectively collected data about adult patients treated with PAZ for metastatic STS in Turkey. We described the clinical characteristics and tumor responses, and estimated the progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. The Cox proportional hazards regression model (HR, 95%CI) was used for evaluation of prognostic factors for PFS. Results: 507 patients (median age: 52 [range: 18-87]; 56.8% female) were included in the analysis. Extremities were the most common primary tumor sites (n:202; 39.8%) followed by abdomen (n:116; 22.9%) and pelvic cavity (n:102;20.1%) where 98% of STSs arose in uterus (n:100). The leading histologic subtypes were leiomyosarcoma (n:192; 37.9%), synovial sarcoma (n:58; 11.4%) and undifferentiated pleomorphic sarcoma (n:48; 9.5%). Of the reported tumor grades (n = 350), 61.4% (n:215) were grade 3. The most common metastatic sites were lungs (52.7%) and liver (20.3%). Doxorubicin plus ifosfamide (45.9%) was the preferred front-line regimen and PAZ was the treatment of choice in second (59.8%) and third-line (61.8%) settings. The median follow-up under PAZ treatment was 5.03 (0.10-84.67) months. Objective response and disease control rates were 31.4% and 42.2%, respectively. Overall, 183 (36.1%) patients were alive at last follow up, 123 of which (67.2%) did not show progression. The median PFS and OS for the study group and the most commonly observed types of STS are shown in Table. Favorable prognostic factors for PFS were low-intermediate tumor grade (HR[95% CI] for grade I and 2 vs 3:1.371[1.016-1.849]; p = 0.039) and ECOG (Eastern Cooperative Oncology Group) score (HR[95% CI] for ECOG score &lt; 2 vs ≥2: 2.698[1.923-3.787]; p = 0.0001). Weakness/asthenia (10.8%), impaired liver function tests (4.7%) and diarrhea (3.6%) were the most common adverse events, no grade 4 or 5 events were observed. Conclusions: This large scale real-life study confirms that PAZ, with its positive impact on clinical outcomes and acceptable tolerability and safety profile is a valuable treatment option for metastatic STS.[Table: see text]

A comparison of dosimetry and clinical outcomes in patients receiving photon external beam therapy to the pelvis: A two-year experience with 6MV and 10MV photon energies in cervical cancer patients at Parirenyatwa Radiotherapy Centre in Harare, Zimbabwe.

e18768 Background: Radiotherapy efficacy depends on the ability of the treatment machine to deliver optimal radiation dose to target volume while sparing normal tissue using different techniques. The photon energy determines penetrative power. Higher photon energies are generally preferred over low photon energies when treating deep tumours using 3-dimensional conformal radiotherapy (3DCRT). In most low income settings, availability of higher energies (≥10MV) is limited. Elsewhere protocols do not recommend use of lower energies for deep pelvic tumours. There is paucity of data comparing 10MV and 6MV photon energy plans and outcomes for treatment of pelvic tumours with 3DCRT. This study aimed to compare dosimetric and clinical tumour outcomes between the two photon energies which are available in our setting when treating locally advanced cervical cancer (LACC). Methods: We retrospectively analysed medical records for LACC patients who received definitive concurrent chemoradiotherapy (CCRT) at Parirenyatwa Group of Hospitals Radiotherapy Centre for the period between 1st January 2017 and 31st December 2018. Patient’s treatment plans were stratified into two arms according to the photon energies used (10MV and 6MV) and their respective dosimetric and clinical tumour outcomes at three months post-treatment were compared. Results: A total 875 cervical cancer patients were seen during the study period, of these 82 met the inclusion criteria and were evaluated. Out of these, 20(24.4%) and 62(75.6%) patients were planned and/or treated with 10MV and 6MV photon energy respectively. The differences in minimum doses to the planned target volume and dose homogeneity index between the two photon energies were statistically significant (p-values 0.027 and 0.028 respectively), whereas the other dosimetric parameters (maximum &amp; average doses to the planned target volume, conformity index and maximum doses to rectum, bladder, femoral heads and bowel) were not statistically significant (p-values of 0.245, 0.309, 0.130, 0.19, 0.35 and 0.42, and 0.16 respectively). Complete clinical tumour response at 3 months post treatment was 95% in the 10 MV arm compared to 91% in the 6 MV arm. Conclusions: This study showed that the dosimetric and clinical tumour outcomes in LACC patients receiving 3DCRT definitive CCRT using 10MV or 6MV photon energy in our setting are comparable. Follow-up prospective studies to further characterise the application of these photon energies in resource constrained settings is recommended.

Radiotherapy in the comprehensive treatment of rectal cancer

Introduction. A favorable outcome of the treatment of patients with rectal cancer in the early stages is not a difficult task, as it is easily solved thanks to only surgical intervention. The biggest problem is the treatment of patients with late-stage (III and IV) rectal cancer. The use of radiation therapy is an integral niche in the complex treatment of rectal cancer. Complete or partial clinical response of the tumor to neoadjuvant therapy is a favorable factor that correlates with an increase in overall and recurrence-free survival of patients with rectal cancer.&#x0D; Aim. To conduct an analysis of the effectiveness of radiotherapy and neoadjuvant chemoradiotherapy in the complex treatment of rectal cancer based on the results of the tumor's clinical response to the treatment.&#x0D; Research results. In both groups of patients, the tumor was localized in the middle ampullary part of the rectum in 52.6% of the main group and 55.4% of the control group. In the lower ampullary section of the rectum in 22 patients of the main group (38.6%) and in 22 (39.3%) of the control group, respectively. The number of patients with tumor localization in the upper ampullary region was 5 (8.8%) and 35 (5.3%), respectively. Positive dynamics in the form of replacement of tumor tissue by fibrosis was observed in 89 (78.7%) patients in the compared groups. A complete clinical response was noted in 2 (3.5%) patients in the main group and in 1 (1.8%) in the control group. In 86 patients in the compared groups, II and III degrees of tumor regression according to TRG grading were recorded in 43 (75.4%) patients in the main group and 43 (76.8%) in the control group.&#x0D; Conclusions. In both groups, the tumor was most often localized in the middle ampullary part of the rectum, 52.6% in the main group and 55.4% of the control group. Positive dynamics in the form of replacement of tumor tissue by fibrosis was observed in 89 (78.7%) patients in the compared groups. A complete clinical response was noted in 2 (3.5%) patients in the main group and in 1 (1.8%) in the control group. Unsatisfactory dynamics in the form of IV and V degrees of tumor regression according to the TRG grading were noted in 12 (21.05%) patients of the main group and in 12 (21.4%) - in the control group.

The impact of metformin use on the outcomes of locally advanced breast cancer patients receiving neoadjuvant chemotherapy: an open-labelled randomized controlled trial

Recently, several clinical trials have attempted to find evidence that supports the anticancer use of metformin in breast cancer (BC) patients. The current study evaluates the anticancer activity of metformin in addition to neoadjuvant chemotherapy (NACT) in locally advanced BC patients. Additionally, we assess the safety and tolerability of this combination and its effect on the quality of life (QoL) of BC patients. Eighty non-diabetic female patients with proven locally advanced BC were randomized into two arms. The first arm received anthracycline/taxane-based NACT plus metformin. The second arm received anthracycline/taxane-based NACT only. Overall response rate (ORR), clinical complete response (cCr), pathological complete response (pCR), and breast conservative rate (BCR) were evaluated between both groups, and correlated with serum metformin concentration. ORR, cCr, pCR, and BCR increased non-significantly in the metformin group compared to the control group; 80.6% vs 68.4%, 27.8% vs 10.5%, 22.2% vs 10.5%, and 19.4% vs 13.2%, respectively. A trend towards cCR and pCR was associated with higher serum metformin concentrations. Metformin decreased the incidence of peripheral neuropathy, bone pain, and arthralgia, although worsened the gastrointestinal adverse events. Metformin combination with NACT has no effect on the QoL of BC patients. Metformin combination with NACT is safe, tolerable, and improves non-significantly the clinical and pathological tumor response of BC patients.

Trans-Arterial Chemoembolization with 50 μm Degradable Starch Microspheres Versus 300-500 μm Drug Eluting Beads in Hepatocellular Carcinoma: A Comparative Analysis of Initial Treatment Outcomes.

Background and Aims:Trans-arterial chemoembolization (TACE) has become a widely accepted treatment in unresectable hepatocellular carcinoma (HCC). We aimed at comparing the efficacy of Degradable Starch Microspheres (DSMs)-TACE with 50 ± 7 µm versus 300–500 μm Drug Eluting Beads (DEB)-TACE in terms of initial clinical and radiological treatment response parameters.Material and Methods:A total of 54 patients with unresectable HCC who underwent DEB-TACE (n = 25) or DSMs-TACE (n = 29) were included in this retrospective study. Baseline demographic and clinical characteristics, duration of follow-up, local recurrence and survival status, as well as treatment outcome including treatment response via modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria, viable and total tumor diameter and serum alpha-fetoprotein (AFP) levels were analyzed in both study groups.Results:No significant difference was noted between the two groups in terms of local recurrence (31.6 vs. 16.7%) or mortality (73.9 vs. 85.7%) rates after 36-month and 12-month follow-up, respectively. DSMs-TACE vs. DEB-TACE was associated with significantly higher complete response rate (27.6 vs. 0.0%, p = 0.011) and significant decrease in serum AFP levels (p = 0.013).Conclusion:Both DSMs-TACE with 50 ± 7 µm microspheres and 300–500 μm DEB-TACE are effective for local control of unresectable HCC. Our findings revealed superiority of DSMs-TACE over DEB-TACEnin terms of initial clinical and radiological tumor response; though no significant difference was noted between the two patient groups in terms of local recurrence or mortality during follow up.

Initial magnetic resonance imaging tumour regression grade (mrTRG) as response evaluation after neoadjuvant treatment predicts sustained complete response in patients with rectal cancer

PurposeReliable predictors of a sustained clinical complete tumour response (cCR) after neoadjuvant therapy in rectal cancer (RC) are lacking. The aim of this study was to determine if the tumour regression grade (TRG) assessed by magnetic resonance imaging (MRI), at the first restaging after neoadjuvant therapy can predict organ preservation, and to estimate the time interval after which surgery should be recommended in patients who remain in near cCR. Materials and methodsEighty-three consecutive patients were assessed by MRI as having a cCR (mrTRG 1) or near cCR (mrTRG 2) after neoadjuvant therapy. Cox proportional hazards regression models and Kaplan-Meier survival analyses were used to determine associations between resection-free survival (RFS) and mrTRG at the first restaging, and in relation to mrTRG with a landmark period. mrTRG and pathological findings were compared in operated patients. ResultsmrTRG 2 at the first restaging significantly predicted poorer RFS during follow up. The best prediction of RFS was mrTRG at landmark 16 weeks after termination of radiotherapy; 42 out of 49 patients (86%) evaluated as mrTRG 1 had cCR at one year of follow up. In contrast, 12 out of 15 patients (80%) evaluated as mrTRG 2 had clinical signs of tumour and were recommended surgery. ConclusionsThe first mrTRG, and to an even greater extent mrTRG at landmark 16 weeks predicts RFS. Patients who remain mrTRG 2 at 5–6 months after radiotherapy with signs of tumour should be recommended surgery. These findings may help in patient counselling and surgical decision-making.

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI.

Simple SummaryNo comprehensive and simple prognostic model based on pretreatment factors exists for patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) undergoing EGFR-tyrosine kinase inhibitors (EGFR-TKIs). A total of 11 independent prognostic factors were identified by multivariate analysis, including performance status, morphology, mutation, stage, EGFR-TKIs, and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. We established a nomogram based on independent pretreatment factors and used it to stratify EGFRm+ NSCLC patients undergoing EGFR-TKI treatment into five different risk groups for survival using recursive partitioning analysis. The performance of this nomogram was good and feasible, providing clinicians and patients with additional information for evaluating therapeutic options.Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of 2190 patients with EGFRm+ NSCLC cancer who were treated with EGFR-TKIs (including gefitinib, erlotinib, and afatinib) at the branches of a hospital group between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) data were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors to create a nomogram for risk stratification. Univariate analysis identified 14 prognostic factors, and multivariate analysis confirmed the pretreatment independent factors, including Eastern Cooperative Oncology Group performance status, morphology, mutation, stage, EGFR-TKIs (gefitinib, erlotinib, or afatinib), and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. Based on these factors, a novel nomogram was created and used to stratify the patients into five different risk groups for PFS and OS using recursive partitioning analysis. This risk stratification can provide additional information to clinicians and patients when determining the optimal therapeutic options for EGFRm+ NSCLC.

Evaluation of Clinical and Radiological Tumour Response during Neo-Adjuvant Breast Cancer Chemotherapy at Yalgado Ouedraogo University Hospital

Background: Neoadjuvant chemotherapy (NAC) is one of the treatment options for breast cancer. Its aim is to significantly reduce the size of the tumour in preparation for surgery. The aim of this work is to analyze the conditions of clinical and radiological evaluation of NAC at the Yalgado Ouédraogo University Hospital (CHUYO). Patients and Methods: This was a descriptive cross-sectional study based on the medical records of patients followed up in the cancer department of the CHUYO from 1 January 2013 to 31 December 2021. All patients followed for histologically proven, non-metastatic breast cancer and having received at least one course of NAC were included in this study. The variables were related to the socio-demographic characteristics of the patients, the indications, the protocols of NAC and the sequences of evaluation of the tumour response (clinical, radiological and anatomopathological). Results: We collected 105 cases. The average age of the patients concerned was 44 years. The most frequent histological type was non-specific invasive carcinoma in 97.1% of cases. Immunohistochemically, triple-negative patients accounted for 51.4%. At the initial stage, all patients underwent clinical exploration. Clinical measurement of the tumour was performed in 70.5% of cases. The radiological size of the tumour was determined by ultrasound in 59.1% of cases. One patient had a breast MRI. Thirty-one patients were lost to follow-up after the initial evaluation. At mid-term and at the end of treatment, clinical tumour size was performed in 38.6% and 45.6% of cases respectively. There was no breast imaging performed at mid- and end-of-treatment. CT scans were performed in all cases at baseline, mid-term and end of treatment for extension assessment but did not mention the breast tumour. The tumour response rate was not recorded. Conclusion: Clinical assessment of tumour response is almost always empirical and not quantified. Medical imaging examinations are prescribed sparingly so as not to compromise the regularity of treatment and patient assessment.

Abstract P199: Tenfibgen nanoencapsulated RNAi feCK2 inhibits protein kinase CK2 and induces apoptosis in feline oral squamous cell carcinomas in vivo

Abstract In an initial safety evaluation in domestic cats suffering from oral squamous cell carcinomas (FOSCC), nine cat subjects were treated IV with 5-6 doses given twice weekly of s50 RNAi feCK2 at either 2 or 20 ug/kg (Cannon et. al., Hu Gene Ther Clin Devel 28(2):80-6, 2017). Treatment was generally well tolerated. In one case, a clear drug-related Grade 3 side effect was rapid tumor death (tumor lysis) resulting in an open wound. This issue has been addressed successfully in separate mice studies with longer, lower-dose SQ regimens. Protein kinase CK2, as a promising target in oncology, plays vital roles in cell growth, proliferation, and suppression of apoptosis (Ahmed et al., Trends Cell Biol 12: 226-30, 2002). Anti-feCK2aa’ is a tumor-targeted 20 nm crystalline capsule bearing single-stranded RNAi oligos against both CK2 catalytic kinase subunits with a ligand-coated shell derived from Tenascin-C (tenfibgen). Tenascin-C is upregulated in multiple solid tumors and is present in tumors throughout their lifecycle. The capsule’s ultrasmall size enables efficient raft-mediated delivery of oligos to the perinuclear space of the target cell, and the ability to reach metastases without reliance on EPR (Unger et. al, Mol Cancer Ther 13:2018-29, 2014). Initial mechanistic work focused on changes in clinically scored IHC of the CK2a subunit in study tumors. In an effort to develop a future working hypothesis, remaining paraffin-embedded tissues were retrospectively examined for both kinase subunits of CK2 as a mixture (CK2aa’), cleaved PARP (CP, apoptosis marker) and Ago2 (critical enzyme required for RNAi drug activity). Previous work in murine models showed variation of Ago2 levels in primary human and xenograft tumors. Further, model xenograft and syngeneic tumors responded with increased Ago2 levels and drug activity upon 10 mg/ml IV priming followed by low-dose SQ treatment (Cancer Res 2016;76(14 Suppl):3746). Using confocal fluorescence microscopy, we observed that decreased post-treatment CK2aa’ and increased CP corresponded positively with clinical tumor responses while non-responders showed an inverse relationship. Examination of arrayed human HNC samples also showed a variation in Ago2 levels but premalignant oral lesions from a human chemoprevention trial did not. These observations suggest a possible future path for feline patient therapy of advanced lesions using Ago2 stratification, potential IV priming and more convenient, longer-term SQ dosing administered by feline caregivers. A path for human therapy may lie through chemoprevention with much to be learned from feline studies. Funding: University of Minnesota Clinical and Translational Sciences Award (1UL1 RR033183-01), NIH SBIR Contract HHSN26120 1300030C, N01-CN-15000, Mod#5, V.A. Merit Review research funds (BX00173 and BX003282) and NCI Award CA150182. Citation Format: Frank G. Ondrey, Gretchen M. Unger, Claire M. Cannon, Janeen H. Trembley, BT Kren, Jaime F. Modiano, Khalil Ahmed. Tenfibgen nanoencapsulated RNAi feCK2 inhibits protein kinase CK2 and induces apoptosis in feline oral squamous cell carcinomas in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P199.

Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling.

Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies. Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology. These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis. We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Application of the &lt;i&gt;in silico&lt;/i&gt; approach in the study of critical genes predicting chemotherapeutic response to oxaliplatin in treatment of prostate cancer (literature reviev)

Prostate cancer is the leading cause of death among men. Existing prognostic factors make it possible to differentiate the degree of malignancy of tumors with high metastatic potential. Currently, the treatment of high-grade tumors is carried out with hormonal therapy, to which taxanes are added, when the malignant neoplasm becomes resistant to castration. Studies with other anti-cancer agents did not take into account the genetic background of the tumors, and most of the trials showed low response rates. The article describes an in silico approach for screening drug candidates that can be used as an alternative to taxanes. Researched 86 genes that distinguish between high and low grade tumors, and identified several genes that correlated with chemosensitivity. As an example, a set of six genes has been proposed the expression levels of which can predict cell sensitivity to oxaliplatin. The study demonstrates the relevance of an approach to the treatment of high-grade prostate cancer and new biomarkers for predicting clinical tumor response.

Associations between clinical characteristics and tumor response to neoadjuvant chemoradiotherapy in rectal cancer

Following standard neoadjuvant chemoradiotherapy and total mesorectal excision, some patients with locally advanced rectal cancer achieve good response (pathological T0–2N0), while others show nonresponse (pathological T3–4N0 or node‐positive). To date, the clinicopathological predictors of good response and the necessity of adjuvant chemotherapy treatment (ACT) in good responders remain unclear. In this retrospective study, clinicopathological characteristics were surveyed to investigate the correlation with good response; furthermore, a propensity score matching (PSM) model was designed to balance the confounding factors between good responders treated with ACT or observation. A total of 2255 patients were enrolled, including 1069 good responders and 1186 nonresponders. The results of the survival analysis showed a good response predicted a better 3‐year prognosis (p < 0.001). The logistic regression analysis showed less advanced T and N stages (T3 vs. T4; N0 vs. N1–2), more neoadjuvant chemotherapy (nCT) cycles (≥4 vs. 1–3), and delayed surgery (≥8 weeks vs. <8 weeks) were independent predictors of a good response (p < 0.05). Especially, patients treated with both more nCT cycles and a delay in surgery included the greatest number of good responders (p < 0.001). For good responders, after PSM (1:3), 235 observation cases were matched to 705 ACT cases. As compared with observation, ACT had no greater impact on prognosis analysis (p > 0.05). In conclusion, more cycles of nCT and a delay in surgery predicted a better response, and the delivery of ACT might be omitted in good responders.

Prediction of axillary response after neoadjuvant chemotherapy in clinical node positive breast cancer.

BackgroundFor clinical lymph node positive (cN+) breast cancer, the false negative rate of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) is high. Prediction of axillary response after NAC may provide a better way of patient selection. Our study was designed to evaluate factors associated with axillary pathologic complete response (ypN0) after NAC, and to assess the accuracy of the published Olga Kantor predictive model.MethodsA total of 406 patients with cN+ breast cancer were enrolled in this study. All patients had received full courses of NAC before undergoing axillary lymph node dissection (ALND). Univariate analyses and multivariate analysis were performed to explore independent predictors of ypN0. Then the Olga Kantor model were validated by the data of patients enrolled. The Olga Kantor model is not ideal because the pathological breast tumor response was not available before surgery, the clinical breast tumor response was assessed in our study as a modification. The accuracy of the validation and modification of Olga Kantor model were assessed by the area under receiver operating characteristic (ROC) curve (AUC).ResultsAge (P=0.004), molecular subtype (P=0.000), tumor grade (P=0.006), clinical tumor response (P=0.000) and Ki-67 (P=0.009) were correlated with ypN0. Age, molecular subtype and the clinical tumor response were independent predictors of ypN0 (P<0.05). In validation and modification model, the AUC values were 0.795 and 0.789, respectively, there were no significant differences between the two models (P=0.536). For model score ≤3, 4–7 and ≥8 in the modification model, the ypN0 rate were 3.9% (2/51), 22.5% (59/262) and 67.7% (63/93), respectively.ConclusionsThe Olga Kantor predictive model had high accuracy predicting ypN0 after NAC. Our modification model achieved the same predictive efficiency but is more feasible for clinical practice. Patients with higher scores were more likely to achieve ypN0, so SLNB might be a better way than ALND. However, more patient data and multicenter cohort trials are needed to verify the study.

Abstract No. 75 Neoadjuvant Yttrium-90 transarterial radioembolization using MIRD dosimetry with resin microspheres

To evaluate clinical outcomes and pathological tumor response in patients who underwent surgical resection after neoadjuvant Yttrium-90 transarterial radioembolization (Y90-TARE) using resin microspheres

Novel SLC12A2-ROS1 Fusion in Non-Small Cell Lung Cancer with a Significant Response to Crizotinib: The Importance of Choosing the Appropriate Next-Generation Sequencing Assay.

Identifying the druggable target is crucial for patients with nonsquamous advanced non‐small cell lung cancer (NSCLC). This article adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2‐ROS1 rearrangement that has not been previously reported in other cancers: a fusion that has clinical and radiological sensitivity to crizotinib. Fluorescence in situ hybridization detected the SLC12A2‐ROS1 fusion and it was confirmed through hybrid capture‐based next‐generation sequencing (NGS); however, the fusion could not be detected by amplicon‐based assay. The success of implementing NGS into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results. Given this patient's response to crizotinib, identifying patients with undescribed ROS1 fusions has important therapeutic implications.Key Points This is the first known description of an SLC12A2‐ROS1 fusion. Considering the patient's clinical features and tumor response observed after crizotinib therapy, the authors confirm that this new rearrangement has relevant clinical impact for patients with non‐small cell lung cancer.The success of implementing next‐generation sequencing (NGS) into routine clinical practice depends on the accuracy of the testing. Different assays and NGS platforms can achieve differing results. Each assay's limitations need to be considered to ensure the quality of precision medicine in clinical practice.