Neoadjuvant Treatment In Patients Research Articles

Efficacy and safety of cisplatin and paclitaxel (PlaTax regimen) in the neoadjuvant treatment of patients with stage II–III triple-negative breast cancer

Background. Treatment results for the patients with stage II–III triple negative breast cancer (TN BC) have to be improved. Not only the new treatment regimens, but new predictive and prognostic factors should to be developed.Materials and methods. We included 98 patients with stage II–III TN BC in our study. We studied efficacy and safety of PlaTax regimen (cisplatin 75 mg / m2 day 1 + paclitaxel 80 mg / m2 days 1, 8, 15, course every 4 weeks) in this cohort of patients. We assessed pathologic response, survival and factors, which were relevant for predicting response and prognose survival.Results. PlaTax regimen is characterized by high efficacy and tolerable toxicity. Clinical efficacy was 85.8 %, pCR achievement was 60.5 %, tpCR achievement was 58.1 %. The regimen has low haematological toxicity (neutropenia III–IV grades – 4.1 %); the most frequent adverse events were polyneuropathy (18.5 %) and decreased renal function (24.5 %). 3-year progression-free survival was 68.4 %, most of the relapses (92 %) occurred during first 2 years. 3 year overall survival was 77.6 %. The most relevant predictive factor was level of Ki-67 ≥50 % (pCR 38.5 % vs. 68.7 %, p = 0.038). pCR achievement was the most important prognostic factor, resulting in improved 3-year progressionfree survival (44.3 % vs. 89.1 %, p <0.0001), and 3-year overall survival (61.5 % vs. 91.6 %, p = 0.001). Not only the residual disease, but also the size of residual tumor was important from prognostic point of view. Other important prognostic factors were size of the tumor, status of regional lymph nodes, grade. Delay in surgical treatment more than a month lead to decreased 3-year progression-free survival: 87.1 % vs. 62.5 % (p = 0.047).Conclusions. Our data suggest that studied regimen could be an option for patients with stage II–III TN BC. The assessment of the predictive and prognostic factors will help improve the treatment results for patients with stage II–III TN BC.

CT in the prediction of margin-negative resection in pancreatic cancer following neoadjuvant treatment: a systematic review and meta-analysis.

We aimed to systematically evaluate the diagnostic accuracy of CT-determined resectability following neoadjuvant treatment for predicting margin-negative resection (R0 resection) in patients with pancreatic ductal adenocarcinoma (PDAC). Original studies with sufficient details to obtain the sensitivity and specificity of CT-determined resectability following neoadjuvant treatment, with a reference on the pathological margin status, were identified in PubMed, EMBASE, and Cochrane databases until February 24, 2020. The identified studies were divided into two groups based on the criteria of R0 resectable tumor (ordinary criterion: resectable PDAC alone; extended criterion: resectable and borderline resectable PDAC). The meta-analytic summary of the sensitivity and specificity for each criterion was estimated separately using a bivariate random-effect model. Summary results of the two criteria were compared using a joint-model bivariate meta-regression. Of 739 studies initially searched, 6 studies (6 with ordinary criterion and 5 with extended criterion) were included for analysis. The meta-analytic summary of sensitivity and specificity was 45% (95% confidence interval [CI], 19-73%; I2= 88.3%) and 85% (95% CI, 65-94%; I2= 60.5%) for the ordinary criterion, and 81% (95% CI, 71-87%; I2= 0.0%) and 42% (95% CI, 28-57%; I2= 6.2%) for the extended criterion, respectively. The diagnostic accuracy significantly differed between the two criteria (p = 0.02). For determining resectability on CT, the ordinary criterion might be highly specific but insensitive for predicting R0 resection, whereas the extended criterion increased sensitivity but would decrease specificity. Further investigations using quantitative parameters may improve the identification of R0 resection. • CT-determined resectability of PDAC after neoadjuvant treatment using the ordinary criterion shows low sensitivity and high specificity in predicting R0 resection. • With the extended criterion, CT-determined resectability shows higher sensitivity but lower specificity than with the ordinary criterion. • CT-determined resectability with both criteria achieved suboptimal diagnostic performances, suggesting that care should be taken while selecting surgical candidates and when determining the surgical extent after neoadjuvant treatment in patients with PDAC.

The prognostic value of CA19-9 response after neoadjuvant therapy in patients with pancreatic cancer: a systematic review and pooled analysis.

Pancreatic cancer (PC) is a highly aggressive and refractory disease, with disappointing 5-year survival rates. Regarding the wide application of neoadjuvant treatment in patients with PC, how the post-neoadjuvant Carbohydrate antigen 19-9 (CA19-9) response could translate into a survival benefit is not clearly understood. We aimed to evaluate the correlation of the CA19-9 response with overall survival (OS) in patients with PC receiving neoadjuvant therapy. An extensive electronic search in PubMed, Embase, and the Cochrane Library was performed to identify relevant articles, from which data relevant to independent correlations of the CA19-9 response with overall survival (OS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). Altogether, 17 eligible studies were identified in the systematic review. Pooled analysis showed that CA19-9 response > 50% (HR, 0.43; 95% CI 0.29-0.56; P < 0.001) and normalization of CA19-9 (HR, 0.52; 95% CI 0.42-0.63; P < 0.001) after neoadjuvant treatment are significantly associated with promising overall survival. The results also showed that optimal CA19-9 response after neoadjuvant treatment was significantly related to a favorable prognosis (HR = 0.49, 95% CI 0.42-0.55, P < 0.001; I2 = 45.1%, P = 0.04). Subgroup analysis revealed there were no prognostic difference between CA19-9 > 50% and normalization of CA19-9 after neoadjuvant treatment (P = 0.338), but the duration of neoadjuvant chemotherapy over 4months was significantly associated with expanded postoperative survival (P = 0.013). Serum CA19‑9 is valuable in determining the effect of neoadjuvant treatment in patients with PC. Post-neoadjuvant CA19-9 response > 50% or CA19-9 normalization was related to a more promising overall survival, suggesting that optimal CA19-9 response may be a suitable prognostic index to guide treatment decisions.

Current view of neoadjuvant chemotherapy in primarily resectable pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is now the 11th most common cancer and in 2018 there were 458,918 new cases worldwide. In the Czech Republic, a total of 2,173 patients were diagnosed in 2015, ranking the second in incidence worldwide. In contrast to other malignancies, recent research has not brought any major breakthrough in the treatment of PDAC and hence the prognosis remains very serious. Radical resection is the only curative approach, but after the initiation of the standard pathological evaluation of the resected tissue, according to the Leeds protocol, 80% of the resections are R1 (resections with microscopically positive margins). The results of studies in patients with borderline resectable or locally advanced PDAC prefer neoadjuvant chemotherapy or chemoradiotherapy. This approach leads to a higher number of radical R0 resections and better survival. For neoadjuvant treatment in patients with primarily resectable PDAC, most results come from retrospective analysis or phase II trials. However, recently, data from three randomized clinical trials with neoadjuvant therapy for resectable PDAC were presented. These results support the use of chemotherapy or chemoradiotherapy prior to surgery. In the trials published to date, there are differences in chemotherapeutic regimens, cytostatic doses, and the definition of resectability. Thus, up-front resection with adjuvant chemotherapy is still the standard of care and a well-designed randomized trial using neoadjuvant therapy is now necessary.

1059P NEMIO: A randomized phase I-II trial evaluating efficacy and safety of dose dense MVAC (ddMVAC) + durvalumab +/- tremelimumab as neoadjuvant treatment in patients with bladder muscle-invasive urothelial carcinoma

1059P NEMIO: A randomized phase I-II trial evaluating efficacy and safety of dose dense MVAC (ddMVAC) + durvalumab +/- tremelimumab as neoadjuvant treatment in patients with bladder muscle-invasive urothelial carcinoma

Neoadjuvant Treatment for Patients With Localized Pancreatic Adenocarcinoma

Neoadjuvant Treatment for Patients With Localized Pancreatic Adenocarcinoma

Efficacy and safety of camrelizumab combined with FOLFOX as neoadjuvant therapy for patients with resectable locally advanced gastric and gastroesophageal junction adenocarcinoma who received D2 radical gastrectomy.

e16549 Background: Neoadjuvant chemotherapy for patients with locally advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC) can improve the overall survival without increasing operation risk. Nowadays, immunotherapy has become a new promising neoadjuvant treatment. Therefore, we intended to evaluate the safety and efficacy of camrelizumab (anti-PD-1 antibody) combined with FOLFOX as the neoadjuvant therapy for patients with locally advanced GC/GEJC who received D2 radical gastrectomy. Methods: Patients who were diagnosed as resectable locally advanced GC/GEJC received the neoadjuvant treatment of camrelizumab and FOLFOX every 2 weeks for 4 cycles. Imaging evaluation was performed in 2-4 weeks after neoadjuvant therapy. Patients who had no progression disease (PD) were recruited. Eligible patients underwent gastrectomy with D2 lymph node dissection through laparotomy or laparoscopic surgery. The primary end points were safety and R0 resection rate. Results: From July 24 2019 to January 31 2020, 15 patients were recruited. The mean age was 57 years. A total of 10(67%) were males and 5(33%) were females. According to AJCC 8th, cT3 and cT4 were confirmed in 7(47%) patients and 8(53%) patients, N1 and N2 in 7(47%) patients and 8(53%) patients, respectively. During operation, intraperitoneal metastases were found in 2 patients. Of the 13 surgeries, only 2 were laparoscopic and the others were laparotomy. The surgical procedures included Roux-en-Y (9, 69.2%), Billroth II (1, 7.7%) and jejunum interposition (3, 23.1%). Thirteen patients underwent gastrectomy with D2 lymph node dissection and all of them were confirmed R0 resection by postoperative pathology results. The mean lymph node yield was 44.1±13.2 nodes, positive lymph node yield was 1.8±2.8 nodes. Duration time of surgery was 186.5±45.5 minutes, mean blood loss was 219.2±109 ml during the operation. Mean hospital stays were 13.2±2.4 days. Only 1 patient experienced grade 3 pneumonia. Neither serious intraoperative complications nor immune-related adverse events both prior and post operation were observed. There was no treatment-related death. Conclusions: Camrelizumab combined with FLOFOX as neoadjuvant treatment for patients with locally advanced GC/GEJC showed acceptable toxicity and promising efficacy with low complications and mortality. Clinical trial information: NCT03939962 .

Neoadjuvant itraconazole (I) in patients (pts) with resectable basal cell carcinoma (BCC): A phase II multistage study.

e22081 Background: Targeting the hedgehog (HH) protein family pathway has consistently shown activity in locally advanced and metastatic BCC. Itraconazole is an affordable agent with known toxicity profile that demonstrates in vitro HH signaling inhibition, suggesting a possible role in BCC treatment. Initial results of a phase 2 study designed to investigate efficacy of Itraconazole as neoadjuvant treatment in patients with resectable BCC are reported. Methods: Eligible pts had biopsy-proven resectable BCC, ECOG PS 0-3, adequate organ function and measurable disease. Dosing of I consisted of 200mg twice daily for 60 days followed by surgery. Simon two-stage design was used to test a null rate of 5% vs. 20% (power = 0.80; α = 0.05, unilateral). If ≥1 of 13 pts in stage 1 have objective response (OR) according to RECIST 1.1 criteria, 14 more pts will be enrolled. If ≥4 of 27 pts have OR, the treatment is worthy of further study. Secondary endpoints include safety and change in Ki-67 and Gli1. Results: Thirteen pts with 14 measurable lesions enrolled from Jan/2018 to Feb/2019; 1 pt was not evaluable, but was included in safety analysis. Demographics and outcomes are summarized in Table. After 60 days of treatment, all patients had R0 resection as primary planned and 1 (8.3%) PR was observed. There were no progressions during the study. OR rate was 8.3%. No grade 3 AE or SAE were reported. 6 pts had grade 1 or 2 AEs at least possibly related to I including depression, headache, GPT elevation, diarrhea, abdominal pain and bilirubin elevation. Conclusions: Itraconazole showed initial anti-tumor activity in pts with resectable BCC, no safety concerns were observed. Study will proceed to Simon’s second stage. Clinical Trial Information: NCT03972748 , 47011715.0.0000.5327 . [Table: see text]

AB028. Assessing the oncotype dx breast recurrence score assay on core biopsy to predict response to neoadjuvant treatment in patients with breast cancer—a systematic review and meta-analysis

AB028. Assessing the oncotype dx breast recurrence score assay on core biopsy to predict response to neoadjuvant treatment in patients with breast cancer—a systematic review and meta-analysis

Abstract P3-11-03: Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer

Abstract Background: Niraparib is a selective poly(ADP-ribose) polymerase 1/2 inhibitor that has demonstrated antitumor activity in advanced triple-negative breast cancer (TNBC) in combination with a programmed cell death 1 inhibitor, with the greatest clinical activity seen in tumors with breast cancer susceptibility gene (BRCA) mutations. Pharmacologically, niraparib has demonstrated a wide volume of distribution and high cell membrane permeability. In breast and ovarian cancer xenograft mouse models, niraparib achieved tumor exposures that were 3.3 times greater than plasma exposure. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCA-mutated breast cancer. The relative concentration of niraparib in tumor versus plasma was also assessed. Methods: Eligible patients were ≥18 years old, with HER2-negative, BRCA-mutated (germline or somatic) resectable breast cancer with a tumor size of ≥1 cm who had not received prior treatment for the current malignancy. Patients received niraparib 200 mg once daily for 2 months. At the end of 2 months, at their treating physician’s discretion, patients proceeded directly to surgery, received additional cycles of niraparib (maximum of 6 months), or received neoadjuvant chemotherapy. The primary endpoint was tumor response rate measured by magnetic resonance imaging (MRI) after 2 months of treatment. Response was defined as a ≥30% reduction in tumor volume from baseline. Secondary endpoints included tumor response rate measured by ultrasound, quantified percent change in tumor volume measured by MRI or ultrasound, pathological complete response, and safety and tolerability. Additionally, niraparib concentrations were measured in tumor and plasma samples using qualified liquid chromatography-tandem mass spectrometry. Results: Twenty-one patients were enrolled. As of June 2019, 18 patients had both an MRI and ultrasound scan at the end of month 2 and were evaluable for response. Ten patients are currently on treatment. The median age of patients was 43 years (range, 21-73). Fourteen patients had a BRCA1 mutation, 6 patients had a BRCA2 mutation, and 1 patient had both. Fifteen patients had TNBC, and 6 patients had hormone receptor-positive disease. All 18 response-evaluable patients had a clinical response after 2 months of treatment by at least one imaging modality; no patient experienced disease progression. Tumor response rate measured by MRI after 2 months of treatment was 89% (n/N = 16/18). Results measured by ultrasound were similar, with a 94% response rate at cycle 2 (n/N = 17/18). The median percent decrease in tumor volume after 2 months of treatment was 88% (range, 26-100%) and 89% (range, 23-100%) as measured by MRI and ultrasound, respectively. In the 5 samples measured thus far, niraparib concentrations in tumor biopsies after 2 months of treatment ranged from approximately 4-131-fold higher than those in corresponding plasma samples. Efficacy and tumor concentration data for all patients will be presented at the meeting. The most common (≥10%) drug-related treatment-emergent adverse events (TEAEs) of any grade were nausea, fatigue, anemia, insomnia, and decreased appetite. The only drug-related grade ≥3 toxicity in ≥10% of patients was anemia (3 patients). Three patients had a dose reduction due to a TEAE; no patient discontinued treatment due to a TEAE. Conclusion: Niraparib was well tolerated and showed promising antitumor activity in the neoadjuvant treatment of patients with localized HER2-negative, BRCA-mutated breast cancer. Niraparib achieved 4-131-fold higher concentrations in tumor than in plasma. Clinical trial information: NCT03329937. Funding: TESARO: A GSK Company (Waltham, MA, USA) sponsored the study. Citation Format: Hyo Han, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, James Reeves, Andre Liem, Adrianna Milillo Naraine, Julie Nangia, David Page, Meghan Duncan, Ming Shan, Yongqiang Tang, Julie R Graham, Leif W Ellisen, Steven Isakoff, Laura Spring. Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-03.

Abstract P4-10-22: Loss of androgen receptor after neoadjuvant anti-HER2 therapy in patients with locally advanced HER2-positive breast cancer

Abstract Background.Androgen receptor (AR) is widely expressed in different breast cancer subtypes. AR plays an important role in promoting the growth of HER2 + breast cancer through cross-talk with HER2 signaling, including WNT7B upregulation, beta-catenin activation, stimulation of HER3 gene transcription, and promotion of HER2/HER3 heterodimerization. Preclinical data have shown that inhibiting AR with enzalutamide results in decreased HER2 phosphorylation and activation of ERK and AKT, without affecting HER2 and HER3 expression; however, the role that inhibiting HER2 with anti-HER2 therapy plays in AR expression and regulation is still unknown. In this study, we sought to identify the influence of anti-HER2 therapy on AR and estrogen receptor (ER) expression after neoadjuvant treatment in patients with locally advanced HER2+ breast cancer. Methods.We retrospectively collected data from 68 patients with locally advanced HER2+ breast cancer who received neoadjuvant treatment with trastuzumab and chemotherapy. AR and ER levels were determined by immunohistochemistry in available initial biopsy specimens and in surgical specimens of all patients with residual disease after neoadjuvant therapy. AR was assessed by Immunohistochemistry (IHC) staining using AR441 antibody from DAKO. Expression in &amp;gt;10% of cells was considered positive. Pathological complete response (pCR) was defined as ypT0/is, ypN0. ROC curve analysis was performed to identify the correlation between AR score and pCR. Results.Twenty-five patients had pretreatment tissue available. Eighteen (72%) were positive for AR staining and 20 (80%) for ER staining. Of the 25 cases, 10 (40%) achieved a pCR and 15 (60%) did not. The median AR score for those with a pCR was higher, 20 (range 0, 80) vs 10 (range 0, 70). The area under the ROC curve was 0.59 (95% confidence interval 0.35, 0.83); we found no statistically significant relationship between AR score and pCR (p = 0.47). All nine cases positive for AR before neoadjuvant therapy who had residual tissue for staining after therapy had negative AR staining after neoadjuvant anti-HER2 therapy. Of 18 cases positive for ER before neoadjuvant therapy who had residual tissue for staining after therapy, only 6 (33%) had negative ER staining after neoadjuvant anti-HER2 therapy. Further, all patients initially positive for AR and ER remained ER positive but were AR negative after therapy. Conclusions. We found that in 100% of cases AR positivity disappeared after anti-HER2 neoadjuvant therapy in patients with residual disease, whereas ER positivity disappeared in only 33% of cases, suggesting that blocking HER2 may inhibit positive feedback with AR; however, both AR and ER receptors have independent biological interactions with HER2 that need to be explored. We plan to confirm our results with a larger sample size, and we will continue to monitor our patients to determine the influence of AR negativity after neoadjuvant anti-HER2 therapy on disease-free and overall survival. Citation Format: Jose Rodrigo Espinosa Fernandez, Aysegul A. Sahin, Kenneth R. Hess, Raul Gerardo Ramirez Medina, Paula Anel Cabrera Galeana, Alejandro Javier España Ferrufino, Nereida Esparza Arias, Juan Enrique Bargallo Rocha, José Antonio García Gordillo, Gerardo Emmanuel Lopez Muñiz, Naoto T Ueno. Loss of androgen receptor after neoadjuvant anti-HER2 therapy in patients with locally advanced HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-22.

Abstract GS2-06: Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: An open-label, multicenter, two-arm, randomized study

Abstract Background: Different approaches for treatment de-escalation are being investigated; however, the current ongoing phase III adjuvant trials with CDK4/6 inhibitors are not addressing the question if these drugs can replace multi-agent chemotherapy in high-risk early breast cancer. Here, we present the primary results of the CORALLEEN phase 2 trial, which evaluates the efficacy of ribociclib plus endocrine therapy (ET) as neoadjuvant treatment in patients with high-risk Luminal B disease. Methods: CORALLEEN is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable hormone receptor-positive (HR+)/HER2-negative breast cancer, Luminal B by Prosigna®. Other eligibility criteria include stage I-III operable breast cancer and ECOG 0-1. Patients were randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy (CT): 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel (80 mg/m2) during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens were collected for molecular characterization and evaluation of response. The primary endpoint is the rate of PAM50 Risk of Relapse (ROR)-low disease at surgery in each arm. PAM50 ROR score integrates gene expression data, tumor size, and nodal status to define a low-risk group in the adjuvant setting (i.e. &amp;gt;90% distant relapse-free survival at 10 years). ROR-low was defined using the standard cutpoints as &amp;lt;40 points if pathologically node-negative (at surgery) and &amp;lt;15 points if 1-3 positive nodes (at surgery). The trial was designed to estimate the rate of ROR-low disease at surgery in each arm without a formal comparison. A total of 47 evaluable patients per arm and an expected ROR-low rate of 25%, would allow a precision of the estimate between 11.5% and 12.4%. Secondary endpoints included safety, intrinsic subtype at surgery, residual cancer burden (RCB), and Preoperative Endocrine Prognostic Index (PEPI). Results: From July 2017 to November 2018, 198 patients were screened with Prosigna® across 21 sites in Spain. From these, 106 (54%) patients with Luminal B disease were recruited, and 96 (90.6%) completed treatment as planned. Main baseline patient characteristics were similar between both treatment arms: mean age 64, mean tumor size 3.8 cm, N+ 39%, mean Ki67 33.2%, and mean ROR score 72.9 (86.8% were ROR-high). A total of 101 (95.3%) surgical samples were analyzed. ROR-low rates at surgery in the ribociclib+ET and CT arms were 48% (95%CI 33.7-62.6) and 47.1% (95%CI 32.9-61.5), respectively. Intrinsic subtype conversion to Luminal A at surgery occurred in 88% of patients in the ribociclib+ET arm and in 84.3% in the CT arm. The rates of RCB0/1 and PEPI 0 in the ribociclib+ET arm were 8% (95%CI 2.2-19.2) and 24% (95%CI 13.1-38.2), respectively. The rates of RCB0/1 and PEPI 0 in the CT arm were 11.8% (95%CI 4.4-23.9) and 17.6% (95%CI 8.4-30.9). Grade 3-4 toxicities were observed in 54.9% of the patients in the ribociclib+ET arm and 69.2% in the CT arm. Additional correlative molecular analyses will be presented. Conclusions: Neoadjuvant ribociclib and letrozole in high-risk Luminal B breast cancer achieves similar rates of ROR-low disease at surgery as multi-agent chemotherapy. Future studies in high-risk early breast cancer evaluating the survival outcomes and quality of life of this combination in the absence of cytotoxic therapy are justified. Citation Format: Joaquín Gavilá, Cristina Saura, Tomás Pascual, Cristina Hernando, Montserrat Muñoz, Laia Paré, Blanca González Farré, Pedro Fernandez, Patricia Galván, Xavier González Farré, Mafalda Oliveira, Miguel Gil Gil, Miriam Arumi, Neus Ferrer Tur, Alvaro Montaño, Yan Izarzugaza, Antonio Llombart Cussac, Raquel Bratos, Santiago González, Eduardo Martínez, Sergio Hoyos, Beatriz Rojas, Juan Antonio Virizuela, Vanesa Ortega, Rafael López, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Aleix Prat. Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: An open-label, multicenter, two-arm, randomized study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-06.

Abstract P4-02-06: Automated molecular diagnosis of suspicious axillary lymph nodes in breast cancer patients

Abstract Background: Axillary lymph node metastasis is associated with a high risk of breast cancer recurrence and is the single most powerful predictor of patient prognosis. Various imaging tests alone or in combination with preoperative fine needle aspiration (FNA) cytology are used to evaluate suspicious lymph nodes (LNs). However, these methods have low sensitivity (70%) and their utility varies depending on the local surgical practice and experience of the cytologists. In previous work, we have demonstrated higher than 90% sensitivity/specificity of a panel of ten hypermethylated biomarkers in FNA to distinguish between cancer and benign breast lesions. Analysis of methylated genes in FNA of suspicious LNs may improve sensitivity of cancer detection and assist in staging disease more accurately. Methods: We used Quantitative Multiplex Methylation-Specific PCR (QM-MSP) to determine the utility of the 10-gene panel for detecting tumor cells in LN FNAs. Two studies were performed to test the accuracy of a newly developed automated, cartridge-based GeneXpert® Breast Cancer Detection Assay (RUO*). First, we conducted a prospective case-control study in China in breast cancer patients with palpable LNs undergoing sentinel lymph node biopsy. FNA specimens were collected intraoperatively from a single palpable LN and assayed. Histopathology of the same LN (88 metastatic and 104 benign), was used as the gold standard for comparison. Next, using the automated assay, a pilot validation study was conducted on archival ultrasound-guided FNAs (69 metastatic and 53 benign by cytopathology) collected preoperatively from enlarged axillary LNs in patients with and without breast cancer in the outpatient centers in China and U.S.A. We calculated sensitivity, specificity and area under the receiver operating characteristic curve (AUC) for the marker panel tested by the GeneXpert® assay compared to histopathology for the case control study, and cytopathology for the pilot validation study. We also compared its performance to the highly sensitive laboratory assay, QM-MSP. Results: In the case-control study in China, compared to histopathology, cytopathology of the palpable enlarged LNs achieved cancer detection sensitivity of 85% and specificity of 95% (ROC; AUC=0.898, 95% CI: 0.843-0.953). Using the GeneXpert® assay on the same samples, compared to histopathology, the methylated biomarker panel showed a sensitivity of 92.0% and a specificity of 98.1% based on receiver operating characteristic statistics (ROC; AUC = 0.960, 95% CI: 0.928-0.993). QM-MSP yielded a similar sensitivity of 91.8% and a specificity of 97.7% (ROC; AUC = 0.966, 95% CI: 0.934-0.998). In the pilot validation set, compared to cytopathology, the automated assay achieved a sensitivity of 94.2% and a specificity of 92.5% (ROC; AUC=0.976 (95%CI: 0.950-1.001). Conclusions: We have developed and piloted a 5-hour, automated GeneXpert® Breast Cancer Detection Assay (RUO*) on FNA to detect cancer in suspicious LNs. This assay performs with an accuracy equivalent to that of the highly sensitive but labor-intensive assay, QM-MSP. This test has the potential to determine axillary involvement with higher sensitivity than cytopathology within a very short time in the outpatient setting. A positive test preoperatively could provide guidance for decision-making regarding eligibility of patients for neoadjuvant treatment, post-mastectomy radiotherapy and breast reconstruction. Further evaluation of this automated assay in larger, blinded, prospective studies is warranted. Citation Format: Juanjuan Li, Bradley Downs, Leslie Cope, Xiuyun Zhang, Chuan-gui Song, Kejing Zhang, Yong Han, Mary Jo Fackler, Edwin Lai, Suzana Tulac, Neesha Venkatesan, Timothy Guzman, Chuang Chen, Jingping Yuan, Saraswati Sukumar. Automated molecular diagnosis of suspicious axillary lymph nodes in breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-06.

Nomogram for predicting pathological complete response and tumor downstaging in patients with locally advanced rectal cancer on the basis of a randomized clinical trial.

BackgroundPreoperative fluoropyrimidine with radiotherapy was regarded as the standard of care for locally advanced rectal cancer (LARC). The model for predicting pCR in LARC patients was based on standard treatment only. This study aimed to establish a nomogram with pretherapeutic parameters and different neoadjuvant regimens for predicting pathologic complete response (pCR) and tumor downstaging or good response (ypT0-2N0M0) after receiving neoadjuvant treatment in patients with LARC based on a randomized clinical trial.MethodsBetween January 2011 and February 2015, 309 patients with rectal cancer were enrolled from a prospective randomized study (NCT01211210). All pretreatment clinical parameters were collected to build a nomogram for predicting pCR and tumor downstaging. The model was subjected to bootstrap internal validation. The predictive performance of the model was assessed with concordance index (C-index) and calibration plots.ResultsOf the 309 patients, 53 (17.2%) achieved pCR and 132 (42.7%) patients were classified as tumor downstaging with ypT0-2N0M0. Based on the logistic-regression analysis and clinical consideration, tumor length (P = 0.005), tumor circumferential extent (P = 0.036), distance from the anal verge (P = 0.019), and neoadjuvant treatment regimen (P < 0.001) showed independent association with pCR following neoadjuvant treatment. The tumor length (P = 0.015), tumor circumferential extent (P = 0.001), distance from the anal verge (P = 0.032), clinical T category (P = 0.012), and neoadjuvant treatment regimen (P = 0.001) were significantly associated with good tumor downstaging (ypT0-2N0M0). Nomograms were developed to predict the probability of pCR and tumor downstaging with a C-index of 0.802 (95% confidential interval [CI], 0.736–0.867) and 0.730 (95% CI, 0.672–0.784). Internal validation revealed good performance of the calibration plots.ConclusionsThe nomogram provided individual prediction responses to different preoperative treatment for patients with rectal cancer. This model might help physicians in selecting an optimized treatment, but warrants further external validation.

Platinum-based drugs in neoadjuvant treatment of patients with triple-negative breast cancer

Platinum-based drugs in neoadjuvant treatment of patients with triple-negative breast cancer

Pegylated liposomal doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy in locally advanced breast cancer (registration number: ChiCTR1900023052)

Anthracyclines have a profound effect on breast cancer. However, at higher dosages, there are many toxic side effects associated with their use; these include bone marrow suppression, alopecia, gastrointestinal reactions and cardiotoxicity. Pegylated liposomal doxorubicin (PEG-LG) has been demonstrated to achieve equivalent efficacy to conventional doxorubicin, with significantly lower cardiotoxicity. We conducted an open-label, multicenter, single-armed clinical trial useing an NAC regimen based on four cycles of PEG-LD 40 mg/m2 plus cyclophosphamide (CPM) 600 mg/m2 on day 1 of a 21 day schedule, followed by four cycles of docetaxel (DTX) 85 mg/m2 on day 1 of a 21 day schedule. The primary endpoint analysed was the pathological complete response rate (pCR) in the breast, while treatment toxicities and safety were also assessed. The results showed that the breast pCR rate was 18.75% (95% CI 11.5–26.0%). Among the different molecular cancer types, the triple negative breast cancer patients had the highest pCR, at 43.75%. No significant decrease in left ventricular ejection fraction was observed. Our data tends to draw the conclusion that this regimen is a viable option for the neoadjuvant treatment of patients with LABC, especially in the triple-negative subtype and patients with heart abnormalities. We believe the efficacy and the safety of this regimen is likely to be the same based on published data from other studies but that this cannot be certain without a randomized trial.

Emerging strategies in neoadjuvant treatment of patients with HER2-positive early breast cancer

The St. Gallen Consensus 2017 recommended neoadjuvant therapy as a standard of care in stage II-III HER2-positive (HER2+) early breast cancer (EBC). Today, the neoadjuvant approach has become even more clinically relevant, as pathological complete response (pCR) status can not only be used to predict patient outcome, but also to escalate anti-HER2 therapy after surgery, based on the recently published results from the KATHARINE trial. Based on the NEOSPHERE results, dual antibody blockade together with chemotherapy has become the neoadjuvant standard. The chemotherapy backbone consists either of an anthracycline-taxane sequence or of an anthracycline-free regimen such as docetaxel and carboplatin. Adjuvant anti-HER2 therapy is then chosen based on initial tumor burden and pCR status. A multidisciplinary approach right from the beginning guarantees optimal treatment results for patients with HER2+ EBC.Emerging strategies will include early response markers (e.g. biomarkers, molecular imaging) as well as novel targeted agents (e.g. immunotherapy) in order to individualize systemic therapy in HER2-positive EBC. Neoadjuvant and adjuvant therapy thus represent components of an integrated, continuous strategy in HER2+ EBC allowing therapy adaptation according to individual tumor response. Refining the treatment algorithm with further de-escalation and escalation approaches will hopefully lead to better chances for cure as well as reduced short- and long-term toxicities in HER2-positive early breast cancer.

987TiP - NEMIO: A randomized phase II trial evaluating efficacy and safety of dose dense MVAC (ddMVAC) + durvalumab +/- tremelimumab as neoadjuvant treatment in patients with bladder muscle-invasive urothelial carcinoma

BackgroundNeoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in non-metastatic muscle-invasive bladder cancer (MIBC). However, 60-75% patients have residual tumor after neoadjuvant cisplatin-gemcitabin or ddMVAC regimen. Pathological complete response (pCR) after NAC is correlated with overall survival (OS). Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe in urothelial carcinoma (UC) in fit patients. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination chemo plus ICI could increase the pCR rate. Trial designNEMIO is a French open-label randomized phase II trial assessing in the neoadjuvant setting the combination ddMVAC plus durvalumab (D) alone or in combination with tremelimumab (T): 4 cycles of ddMVAC every 2 weeks + 2 cycles of D (1500mg) +/- T (75mg) every 4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. As no safety data are available on the ICI plus ddMVAC combination, 6 pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate of the 2 regimens. Each arm will be expanded to a maximum of 60 pts according to a Bayesian stopping rule based on grade 3/4 treatment-related adverse events (G 3/4 TRAE). The primary endpoint of the safety run-in phase will be the rate of G3/4 TRAE. The primary endpoint of the phase II will be the pCR rate and G3/4 TRAE. We hypothesized that pCR after ddMVAC + D +/- T will be > or=45%. Exploratory endpoints will include biomarkers of response and resistance to the combo. Molecular analysis will be conducted on tumor, blood (ctDNA) and urine samples (uDNA). Immunological and metabolomics profile will also be analyzed. Seven patients have yet been enrolled since December 2018 from the 10 French participating centers and we expect the recruitment to be completed in 2021. Clinical trial identificationNCT03549715. Legal entity responsible for the studyAssociation pour la Recherche de Thérapeutiques Innovantes en Cancérologie (ARTIC). FundingAstraZeneca. DisclosureC. Thibault: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. D. Borchiellini: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Ipsen. O. Huillard: Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): Janssen. P. Barthelemy: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Sanofi. D. Pouessel: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Incyte. A. Flechon: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD. H. Blons: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer; Advisory / Consultancy: MSD. S. Oudard: Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self): Roche. All other authors have declared no conflicts of interest.

Abstract 4610: Prognostic impact of KRAS driver mutations and GSTT1 expression in colorectal cancer to FOLFOX treatment

Abstract Colorectal cancer (CRC) is one of the most common cancer and the leading causes of cancer-related death worldwide. CRCs are neoplasms which have high propensity for metastasis, especially spreading to liver and lung. Liver metastasis accounts for around 50% of CRC patients, usually associated with cancer relapse and worse prognosis of the patient. The combination chemotherapy FOLFOX including 5-flurouracil, oxaliplatin and leucovorin is one of the most common and standard first-line chemotherapy utilized for adjuvant and/or neoadjuvant treatment of patients with CRC, which can reduce the risk of cancer relapse. However, a number of studies reported that chemotherapy alone cannot completely eradicate all the cancer cells, especially metastatic cells. Moreover, the mutations of oncogenes such as KRAS, existed in more than 40% of CRC patients, are often associated with poor response of anti-EGFR therapy either as single agent or in combination with FOLFOX. There is still no direct evidence on the association of KRAS or other oncogenic drivers with the resistance to FOLFOX. To understand if any of the potential biomarkers have the predictive value of FOLFOX treatment for CRC patients, especially later stage diseases, we have selected 16 CRC PDX models derived from patients who are in stage II or later where most of patients’ tumors present invasion and metastatic features. We have evaluated the drug efficacy of FOLFOX treatment in vivo for these 16 CRC PDX models and found that 6 of them were sensitive to FOLFOX and 10 models have poor responses. To study the potential biomarkers which affect the efficacy of FOLFOX in CRC PDX models, we analyzed the correlation of tumor growth inhibition (TGI) with the genomic background of these PDX models and identified the genes with significant correlation. Through filtering the genes by their functional relevance to FOLFOX treatment, we found that low expression of GSTT1 was highly related to FOLFOX resistance in these CRC PDX models. GSTT1 deletions was found to enhance the resistance to chemotherapy and a shorter survival in AML patients, which is consistent with our observation. Furthermore, we have also run the driver mutation analysis for these 16 PDX models, and found that models without KRAS driver mutations are more sensitive to FOLFOX treatment. Interestingly, in 32 CRC patients treated with FOLFOX, we found the sensitivity of FOLFOX is correlated with wild type KRAS and high expression of GSTT1, similar to our findings in PDX studies. In conclusion, our studies demonstrated that KRAS driver mutations or low expression of GSTT1 gene may render higher chances of resistance to FOLFOX treatment, these biomarkers may be beneficial for clinicians to choose effective therapies for advance CRC patients. Citation Format: Jessie Jingjing Wang, Binchen Mao, Sheng Guo, Davy Xuesong Ouyang, Henry Qixiang Li. Prognostic impact of KRAS driver mutations and GSTT1 expression in colorectal cancer to FOLFOX treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4610.

Abstract 762: A non-invasive miRNA signature for the identification of pancreatic ductal adenocarcinoma (PDAC) patients with poor molecular subtypes and worse prognosis

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with dismal prognosis. Recent advances in treatment paradigms have been encouraging; however, identification of appropriate patient populations and a better understanding of the underlying tumor heterogeneity could further improve patient outcomes. Recently, four distinct molecular subtypes of PDAC were established, and in particular, squamous subtype was attributed with worse prognosis. Nonetheless, the clinical application of genome-wide transcriptome-based subtyping is cumbersome. Therefore, in this study, we identified miRNA networks regulating the expression of various genes in each PDAC subtype, with a goal to develop tissue and liquid biopsy-based miRNA biomarkers that can be translated into the clinic. Experimental Design: We used a mRNA-miRNA network-based approach to unravel miRNA networks regulating various PDAC subtypes. Using logistic regression models and area under the curve (AUC) analysis, we evaluated the performance of a miRNA-signature for identifying poor molecular subtypes of PDAC. Using qRT-PCR assays, we also analyzed the prognostic significance of the miRNA panel in 433 PDAC patients, including TCGA (n=183), multiple in-house retrospective, tissue cohorts (n=199) and a prospective, preoperative serum cohort (n=51). Univariate and multivariate Cox-proportional hazard models were used for data analysis, and Youden’s index derived cut-off thresholds were used to plot the Kaplan Meier (KM) curves for overall survival. Results: We identified a panel of 9-miRNAs that were significantly dysregulated (upregulated: miR-205-5p and -934; downregulated: miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p and 1251-5p) in squamous subtype; and was highly accurate in identifying all poor molecular PDAC subtypes proposed previously (Squamous AUC=0.90, Basal AUC=0.89 and Quasimesenchymal AUC=0.83). Intriguingly, expression level of all these 9-miRNAs clearly stratified overall survival (OS) in patient subgroups, and patients with high-risk scores exhibited significantly worse OS (Hazard ratio (HR): 2.48, p&amp;lt;0.0001). Intriguingly, our miRNA signature was equally robust even in pre-operative serum specimens for identifying patients with poor OS (HR: 2.85, p=0.02), highlighting its significance for treatment decision-making in the clinic. Conclusions: We for the first time report a unique miRNA signature for identifying patients with poor molecular subtype PDAC who are at risk for worse overall survival. Our 9-miRNA signature can be easily adapted into the clinical setting using simple qRT-PCR based assays. The discrimination of high-risk patients even in the preoperative setting could improve the selection of PDAC patients for neoadjuvant treatment, especially in those with unresectable disease. Citation Format: Raju Kandimalla, Tadanobu Shimura, Saurav Mallik, Susan Tsai, Douglas B. Evans, Hideo Baba, Yasuhiro Kodera, Xi Chen, Ajay Goel. A non-invasive miRNA signature for the identification of pancreatic ductal adenocarcinoma (PDAC) patients with poor molecular subtypes and worse prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 762.