Primary Systemic Treatment Research Articles

IORT-photon boost plus hypofractionated whole breast irradiation in patients with breast cancer after primary systemic treatment: feasibility, safety and clinical results.

To assess for the first time the safety and feasibility of combining photon-intraoperative radiotherapy (ph-IORT) with hypofractionated whole breast irradiation (h-WBI) in patients referred to primary systemic therapy (PST). From March 2019 to December 2020, patients referred for breast conservative surgery (BCS) after PST in our institution were prospectively included in the present trial. PST was prescribed to all patients according the ESMO-SEOM guidelines. Once the PST was completed, BCS was discussed in the multidisciplinary tumor board (MTB). 20Gy were prescribed to the surface of the applicator of an Intrabeam®photon-IORT during BCS. h-WBI (40.5Gy/2.67Gy/15frx) was planned to be administered 3-5w after BCS. All patients were treated with hWBI VMAT-Rapid-Arc&Daily Exac-Trac-IGRT. The primary end points of the study were feasibility and safety (grade 3 toxicity rate CTCAE.5.0-scale) of the proposed treatment protocol. The secondary end points included cosmetic results (Harvard Scale), local relapse rate and overall survival. Thirty-five patients were included in the trial. The median age was 54years. Tumor size was > 2cm in all cases. Eighteen patients were N + (51.4%). There was no disease progression during PST. All patients received the planned 20Gy-ph-IORT boost at the time of BCS and the proposed h-WBI. 31/35 (88,6%) patients started h-WBI within the predefined time period (3-5w after BCS). No patient showed ≥ G3 acute toxicity 3months after the end of h-WBI. No ≥ G3 late toxicity was observed at 12months of follow-up and thereafter. Cosmetic results were scored excellent/good in 26 patients (74.2%). After a median follow-up of 52months, a TNBC patient locally relapsed at 13months of follow-up. We demonstrated for the first time that ph-IORT + hWBI is feasible and safe in patients referred to BCS after PST.

Pulmonary metastasectomy for sarcoma: Insights from a referral-center cohort

IntroductionThe low incidence and heterogeneity of sarcomas limit understanding of their progression in metastatic cases. The use of metastasectomy is debated due to lack of consensus and evidence-based data. This study aimed to identify simple prognostic factors that could contribute to the therapeutic strategy. MethodsWe retrospectively reviewed all patients undergoing pulmonary metastasectomy from sarcoma in our referral center between 2011 and 2022. Demographic, radiologic, pathologic, and operative data were collected. Oncological follow-up, survival, and risk factor analyses were performed. Results192 patients were identified (mean age 49.3 years). Primary sarcoma arose from the trunk (24.6 %) or limbs (75.4 %), and metastases were metachronous in 85.4 % of cases. The median number of operated lesions was 2, and anatomic resection were performed in 24.1 %. The postoperative course was uneventful in 91.3 % of cases. Post-operative chemotherapy followed lung resection in 68.7 %. 1-, 3-, and 5-year Overall Survival (OS) were 89.6 %, 69.8 %, 57.6 %, respectively, with a plateau phase beyond 5 years. Higher grade or trunk location of the primary sarcoma, incomplete or anatomic pulmonary resection, and post-operative systemic treatment were significantly associated with shorter OS. No histological subtype significantly impacted OS. Location of the primary, resection type, and post-operative systemic treatment independently influenced OS. Non-anatomic and repeated pulmonary resections, were independently associated with “long surviving”. ConclusionIn metastatic sarcoma, pulmonary resections offer prolonged survival in selected patients, supporting its essential role in the whole therapeutic strategy. Anatomic and sequential metastasectomy should be cautiously discussed.

Patients with stage IV colorectal carcinoma selected for palliative primary tumor resection and systemic therapy survive longer compared with systemic therapy alone - A retrospective comparative cohort study.

To compare the survival of palliative stage IV colorectal cancer patients selected for primary tumor resection and systemic treatment (PTR+SYST) to patients with systemic treatment only (SYST). About 20-25% of all colorectal cancer patients are diagnosed with stage IV disease. The benefit of primary tumor resection in the palliative situation is therefore of high concern. However, empirical evidence from randomized and observational studies is inconsistent. Mortality after PTR and systemic treatment was compared to systemic treatment alone in a retrospective observational cohort of patients diagnosed 2012-2020 from the cancer registry in the federal state of Brandenburg (Germany), excluding patients with rectal cancer of the lower two-thirds, emergency procedures, unknown ECOG status, ECOG >2, unknown metastatic status or unclear grading. Of 480 patients, 416 died during an average follow-up of 23 months in mean. 12-months survival was 75% after PTR+SYST compared with 49% after SYST (HR=0.39, 95% CI 0.29-0.53, P<0.001). The difference persisted to 36 months (28% vs. 13%, HR=0.53, 95% CI 0.43-0.66, P<0.001). Results were similar after multivariate adjustment, propensity score matching and delayed entry. Patients with stage IV colorectal carcinoma who are selected for primary tumor resection in combination with systemic therapy and who receive such treatment survive longer compared with patients who receive only systemic treatment. Whether the difference is due to selection of patients or PTR remains unclear. At present, current practice of selecting patients for PTR appears to do no harm.

Disección axilar dirigida tras tratamiento sistémico primario en cáncer de mama N1. Validación de la técnica y experiencia a los 4 años

ObjectivesTo assess the omission of systematic axillary lymphadenectomy (ALND) in patients with N1 breast cancer with axillary pathological response (APR) after primary systemic treatment (PST). Description and experience of the Technique: Target Axillary Dissection TAD. Identify which subtypes are associated with higher APR. Patients and methodsA descriptive, retrospective study of 90 patients with cT1-T3/N1/M0 stage breast carcinoma who received TSP at the Valencian Institute of Oncology (IVO), between January 2020 and December 2023; 63 received chemotherapy and/or anti-HER2 therapy and 27 received hormonal therapy. Biopsy and labeling of the suspicious lymph node (maximum 3) were performed. In the surgery, a harpoon was placed in the axillary lymph node and the sentinel lymph node (BSGC) technique was also performed with technetium-99m and methylene blue. ResultsAPR was achieved in 46/90 cases (51.2%), in 30/46 (65.2%) pCR, and in 16/46 ITC (isolated tumor cells) or micrometastases remained. Macrometastases were observed in 44/90 (48.8%) and therefore ALND or axillary Rt was performed. There have been no axillary or distant relapses. Detection of the marked node: 100%. RPA occurred in: Luminal A, 26%; Luminal B, 42%; HER2-positive, 86% and Triple Negative, 66%. ConclusionsIn the IVO, ADT is a feasible technique. More than 50% of the cohort had an APR avoiding ALND. The HER2-positive and triple negative subtypes have the highest response rate. It is an oncologically safe procedure; NOT less than ALND.

Oncologic outcome of response-guided axillary treatment in patients with cN1 breast cancer after primary systemic therapy.

514 Background: In breast cancer, the majority of clinically node positive (cN1) patients are treated with primary systemic treatment (PST), with increasing rates of axillary pathologic complete response (pCR). Evidence supporting tailoring axillary treatment according to the response is growing. However, it is still debatable whether ALND is beneficial in cN1 patients with residual nodal disease and if any further axillary treatment is necessary in patients achieving pCR. In this study, we present the four-year oncologic outcome of cN1 patients undergoing either axillary radiation treatment or no axillary treatment according to the ‘Marking Axillary lymph nodes with Radioactive Iodine seeds’ (MARI)-protocol. Methods: Between 2014 and 2021, we prospectively enrolled patients with node positive breast cancer and 1 - 3 involved axillary lymph nodes on FDG-PET/CT pre-PST, who were treated according to the MARI-protocol. Patients with residual disease of the MARI node (ypN1) received axillary radiotherapy (RT), while patients with a pCR of the MARI node (ypN0) received no further axillary treatment. The primary endpoint was the axillary recurrence rate. Secondary endpoints include invasive disease free survival (iDFS) and overall survival (OS), calculated using the Kaplan-Meier method. Results: Of the 367 included patients, more than half (54%, n= 198) had hormonal receptor positive (HR+)/Human Epidermal growth factor 2 negative (HER2-) breast cancer; 59 patients (16%) had HR+/HER2+; 39 patients (11%) had HR-/HER2+ and 71 patients (19%) had triple negative (TN) subtype. Median age was 49 (IQR 41 – 56) years. 231 (63%) patients who had ypN1 received RT and 136 patients (37%) who achieved ypN0 received no further axillary treatment. Median follow up was 49 (IQR 32 – 70) months. Axillary recurrence rate was 3.5% ( n= 8) in patients with ypN1 and 0.7% ( n= 1) in patients with ypN0. Most axillary recurrences ( n= 6) occurred simultaneously with distant metastases in the ypN1 group. In patients with ypN1, the iDFS was 86% and the OS 93%; in ypN0 patients, the iDFS was 93% and the OS 98%. Conclusions: Response-guided axillary treatment in patients with limited nodal disease according to the MARI protocol is associated with favorable oncologic outcome without performing ALND’s. De-escalation can therefore be considered safe. [Table: see text]

Abstract PO2-23-04: Magnetic Seeds, used to Locate the Metastatic Axillary Lymph Node placed before Neoadjuvant Chemotherapy for Breast Cancer Treatment, do not interfere the pre-surgical MRI Breast response assessment

Abstract Background: Axillary management in clinically node-positive patients who converted to ycN0 after neoadjuvant chemotherapy (NAC) for breast cancer (BC) remains under research with the aim of de-escalation of axillary lymph node dissection (ALND). A magnetic seed is one of the several positive lymph nodes marking techniques used in targeted axillary dissection (TAD) for patients with cN1 breast cancer undergoing neoadjuvant systemic therapy. It has been criticized for its potential masking effect due to the artefact it produces in the MRI sequences used to assess a proper breast response. This study evaluates if the magnetic seeds placed before NAC for guided TAD have influenced in the breast MRI response assessments. Methods: From October 2021 to June 2023, patients with cT0-4 cN1 breast cancer who were candidates for primary systemic treatment were prospectively recruited. Once a breast lesion and axillary node positivity were confirmed, a based hydrogel marker and a magnetic seed, respectively, were placed prior NAC. Once systemic treatment was completed, imaging techniques were used to assess the response, with MRI being the imaging technique of choice to assess breast response and axillary ultrasound the imaging technique of choice to assess axillary response. Surgical pathological confirmation of response in the axilla was by TAD, including sentinel lymph node and magnetic clipped node resection. Results: A total of 43 patients were included and their characteristics are shown in Table 1. In 16 patients (37%) the tumour was located in the upper outer quadrant (UOQ). In this group, the susceptibility artefact produced by the magnetic seed in the MRI created a black hole obscuring the axilla with a mean diameter of 69 mm (range: 57-76 mm). In no case did the halo interfere with the correct MRI visualisation of the breast marker. By MRI, the mean distance of the artifact halo from the breast marker or residual breast lesion was 40 mm (range: 13-79 mm). Overall, complete radiological response (ycCR) was reported in 20 patients (46%), breast only in 21 (49%) and axilla only in 38 (88%) patients. In 5 patients, preoperative axillary ultrasound revealed residual axillary disease, confirmed by FNA, lead to direct ALND. In the remaining 38 patients the axillary TAD assessment was completed. In all cases, the magnetic clipped node was successfully surgically removed. Pathological complete response (pCR) was confirmed in 9 (21%), breast only in 11 (26%) and axilla only in 13 (30%) patients. MRI diagnostic performance in detecting residual breast disease after NAC was not altered by the magnetic clipped node artifact when comparing the tumour location in the UOQ to the other quadrants (AUC 0.764 vs. 0.702; p=0.698). Conclusions: Surgical axillary staging remains the most reliable method for assessing the axillary response after NAC. Target axillary dissection guided by magnetic seed placed before NAC is an effective and accurate technique. The artifact generated in the MRI does not interfere with the pre-surgical breast response assessment after neoadjuvant systemic treatment. Table 1: Patients and tumor characteristics Citation Format: Martin Espinosa-Bravo, Joaquin Rivero Deniz, Clara Morales Comas, Javier de la Torre Fernandez de Vega, Irene Vives Rosello, Enrica Esposito, Vicente Peg Camara, María De Les Neus Rus Calafell, Ignacio Miranda Gomez, Christian Siso Raber. Magnetic Seeds, used to Locate the Metastatic Axillary Lymph Node placed before Neoadjuvant Chemotherapy for Breast Cancer Treatment, do not interfere the pre-surgical MRI Breast response assessment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-04.

Patients with hepatocellular carcinoma extrahepatic metastases can benefit from hepatic arterial infusion chemotherapy combined with lenvatinib plus programmed death-1 inhibitors.

Lenvatinib plus programmed death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy. This multicenter cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n =127) or LEN-P alone ( n =103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P <0.001; mPFS: 8.0 months vs. 3.0 months, P =0.001). After IPTW, the mOS [hazard ratio (HR)=0.384, P <0.001] and mPFS (HR=0.507, P <0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group's objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P <0.001; IPTW cohort: 66.1% vs. 27.8%, P <0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group ( P >0.05). HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management.

14 Oral - Omission of axillary lymph node dissection in cN2-3 breast cancer patients with an excellent response on primary systemic treatment is safe: 4-year oncologic outcome of the MARI protocol

14 Oral - Omission of axillary lymph node dissection in cN2-3 breast cancer patients with an excellent response on primary systemic treatment is safe: 4-year oncologic outcome of the MARI protocol

Prognostic value of the CRM status in pancreatic ductal adenocarcinoma: Data from a regional cancer registry.

632 Background: Ductal pancreatic adenocarcinoma (PDAC) still has a dismal prognosis even when deemed resectable. A cancer free resection margin (R0) is associated with a more favourable prognosis than the presence of tumour cells at resection margin (R1). However, the precise definition of the R0 status is still a matter of debate in PDAC. For a more accurate determination of R0 in PDAC the concept of circumferential resection margins (CRM) has been introduced. However, an international standardized nomenclature of CRM is still missing, and the clinical value of the CRM concept is not yet fully established. Here we evaluate whether the CRM status as defined in the national German S3 guideline is an independent prognostic factor in PDAC using data from the regional cancer registry of the State of Baden Württemberg in Germany. Methods: Data from the cancer registry of the State of Baden-Württemberg, Germany were collected, using documented patients diagnosed with invasive ductal adenocarcinoma of the pancreas between 2015 and 2020. The R-status was assessed according to the national German S3 guideline with R0 wide/CRM- when CRM is &gt; 1mm, R0 narrow/CRM+ when CRM is £ 1 mm from the tumour and R1 when tumour cells are found at the resection margin. Progression free survival (PFS) as well as 3-year overall survival (OS) were assessed using Kaplan-Meier statistics and multivariable Cox regression models (adjusted for age, pN stage, primary tumor location and systemic treatment). Results: In total we identified 1098 cases surgically treated for pancreatic cancer and fulfilling the inclusion criteria. 340 patients had an R0 wide/CRM- resection, 410 patients an R0 narrow/CRM+ resection, and 348 patients an R1 resection. The R0 wide/CRM- status was associated with a significantly increased median 3-year OS rate compared to the other two groups (51,5%, 37,4% and 26,7% for R0 wide/CRM-, R0 narrow/CRM+ and R1, respectively). mPFS was also longer in the R0 wide/CRM- group. These findings were robust with regards to grading. 5-FU based adjuvant treatment was mainly mFOLFIRINOX and show better outcome as compared to gemcitabine-based treatments. Conclusions: The present study was performed using real world data reflecting actual clinical settings. The results obtained are in good agreement with data from clinical trials, including the prognostic role of the R- and N- Status as well as the efficacy of adjuvant chemotherapy protocols used.

Factors influencing receipt and time to treatment of immunotherapy relative to chemotherapy in stage III and stage IV melanoma.

Immunotherapies have changed the landscape of late-stage melanoma; however, data evaluating timely access to immunotherapy are lacking. A retrospective cohort study utilizing the National Cancer Database was conducted. Stage III and IV melanoma cases diagnosed between 2011 and 2018 that received systemic treatment with either immunotherapy or chemotherapy were included. Chemotherapy included BRAF/MEK inhibitors. Multivariable logistic regression models were utilized to evaluate factors associated with the likelihood of receiving immunotherapy as primary systemic treatment relative to chemotherapy; additionally, Cox proportional hazards models were utilized to incorporate time from diagnosis to primary systemic therapy into the analysis. The study population was comprised of 14,446 cases. The cohort included 12,053 (83.4%) immunotherapy and 2393 (16.6%) chemotherapy cases. In multivariable logistic regression analysis, factors significantly associated with immunotherapy receipt included population density, circle distance, year of diagnosis, Breslow thickness, and cancer stage. Immunotherapy timing was evaluated using multivariable Cox regression analysis. Minorities were less likely to receive timely immunotherapy than non-Hispanic Whites (HR 0.83, CI 0.74-0.93, p = 0.001). Patients at circle distances of 10-49 miles (HR 0.94, CI 0.89-0.99, p = 0.02) and ≥50 miles (HR 0.83, CI 0.77-0.90, p < 0.001) were less likely to receive timely immunotherapy. Patients traveling ≥10 miles and minorities have a decreased likelihood of receiving timely immunotherapy administration for primary systemic treatment. Future research is needed to identify what barriers and approaches can be leveraged to address these inequities.

Comparison of Short-Term Outcomes and Safety Profiles between Androgen Deprivation Therapy+Abiraterone/Prednisone and Androgen Deprivation Therapy+Docetaxel in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer.

This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). A web-based database system was established to collect prospective cohort data for patients with mHSPC in Korea. From May 2019 to November 2022, 928 patients with mHSPC from 15 institutions were enrolled. Among these patients, data from 122 patients who received ADT+abiraterone/prednisone or ADT+docetaxel as the primary systemic treatment for mHSPC were collected. The patients were divided into two groups: ADT+abiraterone/prednisone group (n=102) and ADT+docetaxel group (n=20). We compared the demographic characteristics, medical histories, baseline cancer status, initial laboratory tests, metastatic burden, oncological outcomes for mHSPC, progression after mHSPC treatment, adverse effects, follow-up, and survival data between the two groups. No significant differences in the demographic characteristics, medical histories, metastatic burden, and baseline cancer status were observed between the two groups. The ADT+abiraterone/prednisone group had a lower prostate-specific antigen (PSA) progression rate (7.8% vs. 30.0%; p=0.011) and lower systemic treatment discontinuation rate (22.5% vs. 45.0%; p=0.037). No significant differences in adverse effects, oncological outcomes, and total follow-up period were observed between the two groups. ADT+abiraterone/prednisone had lower PSA progression and systemic treatment discontinuation rates than ADT+docetaxel. In conclusion, further studies involving larger, double-blinded randomized trials with extended follow-up periods are necessary.

First-in-human study of SBRT and adenosine pathway blockade to potentiate the benefit of immunochemotherapy in early-stage luminal B breast cancer: results of the safety run-in phase of the Neo-CheckRay trial

BackgroundLuminal B breast cancer (BC) presents a worse prognosis when compared with luminal A BC and exhibits a lower sensitivity to chemotherapy and a lower immunogenicity in contrast to non-luminal...

Single-Stage Immediate Breast Reconstruction with Acellular Dermal Matrix after Breast Cancer: Comparative Study and Evaluation of Breast Reconstruction Outcomes.

We evaluate postoperative complications, aesthetic results and satisfaction outcomes in patients with breast cancer after intervening with a skin-sparing or nipple-sparing mastectomy with an immediate prosthetic reconstruction with or without a biological mesh. Patients with multifocal breast cancer, ductal carcinoma in situ with an indication for a mastectomy and cT2 tumors with no response to primary systemic treatment were included, whereas patients aged >75 years, with inflammatory carcinoma, and severe circulatory disorders were excluded. Patients in the control group were reconstructed using a prosthesis, whereas the study group included patients reconstructed using a prosthesis and biological acellular porcine dermal mesh (Strattice™). In both groups, the result was assessed using the BREAST-Q instrument. A total of 51 patients (62 intervened breasts) were included in the study group and 38 patients (41 intervened breasts) in the control group. Implant loss and removal occurred in three patients in the study group (5.9%) and nine patients in the control group (24.3%; p = 0.030). Infections appeared in three patients in the study group (4.8%) and three patients in the control group (7.3%; p = 1.00). Skin necrosis appeared in 5 patients in the study group (12.2%) and 11 patients in the control group (21.6%; p = 0.367). Seroma appeared in five patients in the study group (12.2%) and five patients in the control group (8.1%; p = 0.514). The BREAST-Q questionnaire is a comparison between both groups regarding "satisfaction with breasts after surgery" (p = 0.026), "sexual well-being after intervention" (p = 0.010) and "satisfaction with the information received" (p = 0.049). We have noted a statistically significant decrease in implant loss in women receiving an implant with a biological mesh. A higher satisfaction was observed in patients reconstructed using Strattice™, with statistically significant differences in three items.

This house believes that: MARI/TAD is better than sentinel node biopsy after PST for cN+ patients.

The increasing use and effectiveness of primary systemic treatment (PST) enables tailored locoregional treatment. About one third of clinically node positive (cN+) breast cancer patients achieve pathologic complete response (pCR) of the axilla, with higher rates observed in Human Epidermal growth factor Receptor (HER)2-positive or triple negative (TN) breast cancer subtypes. Tailoring axillary treatment for patients with axillary pCR is necessary, as they are unlikely to benefit from axillary lymph node dissection (ALND), but may suffer complications and long-term morbidity such as lymphedema and impaired shoulder motion. By combining pre-PST and post-PST axillary staging techniques, ALND can be omitted in most cN+patients with pCR. Different post-PST staging techniques (MARI/TAD/SN) show low or ultra-low false negative rates for detection of residual disease. More importantly, trials using the MARI (Marking Axillary lymph nodes with Radioactive Iodine seeds) procedure or sentinel lymph node biopsy (SLNB) as axillary staging technique post-PST have already shown the safety of tailoring axillary treatment in patients with an excellent response. Tailored axillary treatment using the MARI procedure in stage I-III breast cancer resulted in 80% reduction of ALND and excellent five-year axillary recurrence free interval (aRFI) of 97%. Similar oncologic outcomes were seen for post-SLNB in stage I-II patients. The MARI technique requires only one invasive procedure pre-NST and a median of one node is removed post-PST, whereas for the SLNB and TAD techniques two to four nodes are removed. A disadvantage of the MARI technique is its use of radioactive iodine, which is subject to extensive regulations.

Real de-escalation or escalation in disguise?

The past two decades have seen an unprecedented trend towards de-escalation of surgical therapy in the setting of early BC, the most prominent examples being the reduction of re-excision rates for close surgical margins after breast-conserving surgery and replacing axillary lymph node dissection by less radical procedures such as sentinel lymph node biopsy (SLNB). Numerous studies confirmed that reducing the extent of surgery in the upfront surgery setting does not impact locoregional recurrences and overall outcome. In the setting of primary systemic treatment, there is an increased use of less invasive staging strategies reaching from SLNB and targeted lymph node biopsy (TLNB) to targeted axillary dissection (TAD). Omission of any axillary surgery in the presence of pathological complete response in the breast is currently being investigated in clinical trials. On the other hand, concerns have been raised that surgical de-escalation might induce an escalation of other treatment modalities such as radiation therapy. Since most trials on surgical de-escalation did not include standardized protocols for adjuvant radiotherapy, it remains unclear, whether the effect of surgical de-escalation was valid in itself or if radiotherapy compensated for the decreased surgical extent. Uncertainties in scientific evidence may therefore lead to escalation of radiotherapy in some settings of surgical de-escalation. Further, the increasing rate of mastectomies including contralateral procedures in patients without genetic risk is alarming. Future studies of locoregional treatment strategies need to include an interdisciplinary approach to integrate de-escalation approaches combining surgery and radiotherapy in a way that promotes optimal quality of life and shared decision-making.

Primary tumor resection or systemic treatment as palliative treatment for patients with isolated synchronous colorectal cancer peritoneal metastases in a nationwide cohort study

Limited data are available to guide the decision-making process for clinicians and their patients regarding palliative treatment options for patients with isolated synchronous colorectal cancer peritoneal metastases (CRC-PM). Therefore, the aim of this study is to analyze the outcome of the different palliative treatments for these patients. All patients diagnosed with isolated synchronous CRC-PM between 2009 and 2020 (Netherlands Cancer Registry) who underwent palliative treatment were included. Patients who underwent emergency surgery or curative intent treatment were excluded. Patients were categorized into upfront palliative primary tumor resection (with or without additional systemic treatment) or palliative systemic treatment only. Overall survival (OS) was compared between both groups and multivariable cox regression analysis was performed. Of 1031 included patients, 364 (35%) patients underwent primary tumor resection and 667 (65%) patients received systemic treatment only. Sixty-day mortality was 9% in the primary tumor resection group and 5% in the systemic treatment group (P = 0.007). OS was 13.8 months in the primary tumor resection group and 10.3 months in the systemic treatment group (P < 0.001). Multivariable analysis showed that primary tumor resection was associated with improved OS (HR 0.68; 95%CI 0.57–0.81; P < 0.001). Palliative primary tumor resection appeared to be associated with improved survival compared to palliative systemic treatment alone in patients with isolated synchronous CRC-PM despite a higher 60-day mortality. This finding must be interpreted with care as residual bias probably played a significant role. Nevertheless, this option may be considered in the decision-making process by clinicians and their patients.

Abstract 2263: Complete remission of a patient with Merkel cell carcinoma treated with durvalumab

Abstract Merkel cell carcinoma (MCC) is a rare, cutaneous, neuroendocrine tumor that is highly aggressive. It is the second leading cause of death from skin cancer, after melanoma, despite accounting for less than 1% of malignant skin tumors. Due to the characteristic histopathological neuroendocrine features of the neoplasm, cases of MCC are often misdiagnosed as undifferentiated skin cancers or other tumors with small blue cell types. Clinical examination fails to establish the diagnosis in 99% of cases and pathological assessment by biopsy with immunohistochemistry is essential to confirm MCC diagnosis. Historically, cytotoxic chemotherapy combinations with platinum-based agents (Carboplatin or Cisplatin) plus Etoposide or Cyclophosphamide, Epirubicin, and Vincristine (CAV) agents were the primary systemic treatment for advanced cases. Despite available evidence sensitivity of MCC to chemotherapy, responses are not durable, and the literature is not supportive of combination chemotherapy (NCCN guidelines). The introduction of immunotherapy such as checkpoint inhibitors (ICI) particularly PD-1/PD-L1 blockers increased overall survival and achieved durable tumor regression in clinical trials leading to FDA approval in locally advanced and metastatic disease. Permbrluzimab and Avelumab are the only two FDA-approved ICIs as first-line standard-of-care treatments for MCC patients. What we are missing is data or trials examining the efficacy of other ICI such as Durvalumab, (anti-PD-L1) in MCC. We hereby report an unprecedented case of an 84-year-old female MCC patient with extensive axillary nodal involvement achieving complete remission after treatment with Durvalumab combined with Carboplatin and Etoposide. Citation Format: Saad Sabbagh, Barbara Dominguez, Houssein Abdul Sater. Complete remission of a patient with Merkel cell carcinoma treated with durvalumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2263.

Abstract 1753: Functional inhibition of the RNA-binding protein HuR sensitizes triple-negative breast cancer to chemotherapy

Abstract The 5-year relative survival rate for triple-negative breast cancer (TNBC) is 77%, which is notably lower than 90%, the overall survival rate for breast cancer. The primary systemic treatment for TNBC remains to be chemotherapy. However, patients frequently develop resistance to conventional chemotherapy, greatly compromising the anti-tumor effects of chemodrugs. Therefore, this study is aimed to enhance the effects of chemotherapy. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. HuR post-transcriptionally regulates the stability of the target mRNA by binding to the U- or AU-rich elements (ARE) mainly in the 3’ untranslated region (UTR) of mRNA. In most cases, the binding stabilizes mRNA, thereby enhancing the translation of the encoded protein, many of which are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, and accumulated cytoplasmic expression, are reported to be related to chemoresistance in many types of cancer cells. We hypothesized that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins contributing to chemoresistance.Previously, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. To test our hypothesis, we utilized KH-3 as a tool compound to assess whether HuR inhibition enhances the efficacy of chemotherapy for TNBC cells. We generated a cell sub-line (231-TR) derived from the human TNBC cell line MDA-MB-231 with acquired resistance against docetaxel (TXT). Compared with the parental cell line, 231-TR exhibited similar sensitivity to KH-3 in the MTT-based cytotoxicity assay and the colony formation assay. The in vitro and in vivo combination of KH-3 and TXT synergized in inhibiting cell proliferation and tumor growth of multiple TNBC cell lines. Regarding mechanisms of action, the apoptosis pathway was downregulated and the Wnt signaling pathway was upregulated in 231-TR cells. KH-3 treatment downregulated β-Catenin, involved in promoting cell proliferation, in a time and dose-dependent manner. KH-3 was also identified to induce apoptosis cell death via inhibiting the anti-apoptotic protein BCL2. The cell cycle analysis revealed that KH-3 treatment caused the S phase accumulation. Therefore, the cell proliferation inhibition by KH-3 results from a combination of apoptosis and cell cycle arrest. Furtherly, KH-3 restored the effects of docetaxel in inducing apoptotic cell death in 231-TR cells. Together, this study provides a new strategy to overcome chemotherapy resistance in TNBC cells by functional inhibiting HuR. Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny Welch, Xiaoqing Wu, Liang Xu. Functional inhibition of the RNA-binding protein HuR sensitizes triple-negative breast cancer to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1753.

P222 Systemic inflammation markers as predictors of axillary clearance: a multicenter analysis on 1274 nodal positive breast cancer patients undergoing primary systemic treatment

P222 Systemic inflammation markers as predictors of axillary clearance: a multicenter analysis on 1274 nodal positive breast cancer patients undergoing primary systemic treatment

Abstract P1-13-08: Inhibition of RNA binding protein HuR function sensitizes the TNBC to chemotherapy

Abstract The 5-year relative survival rate for triple-negative breast cancer (TNBC) is 77%, which is notably lower than 90%, the overall survival rate for breast cancer. The primary systemic treatment for TNBC remains to be chemotherapy. However, patients frequently develop resistance to conventional chemotherapy, greatly compromising the anti-tumor effects of chemodrugs. Therefore, this study is aimed to enhance the effects of chemotherapy. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. HuR post-transcriptionally regulates the stability of the target mRNA by binding to the U- or AU-rich elements (ARE) mainly in the 3’ untranslated region (UTR) of mRNA. In most cases, the binding stabilizes mRNA, thereby enhancing the translation of the encoded protein, many of which are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, and accumulated cytoplasmic expression, are reported to be related to chemoresistance in many types of cancer cells. We hypothesized that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins contributing to chemoresistance. Previously, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. To test our hypothesis, we utilized KH-3 as a tool compound to assess whether HuR inhibition enhances the efficacy of chemotherapy for TNBC cells. We generated a cell sub-line (231-TR) derived from the human TNBC cell line MDA-MB-231 with acquired resistance against docetaxel (TXT). Compared with the parental cell line, 231-TR exhibited similar sensitivity to KH-3 in the MTT-based cytotoxicity assay and the colony formation assay. The in vitro and in vivo combination of KH-3 and TXT synergized in inhibiting cell proliferation and tumor growth of multiple TNBC cell lines. Regarding mechanisms of action, the apoptosis pathway was downregulated and the Wnt signaling pathway was upregulated in 231-TR cells. KH-3 treatment downregulated β-Catenin, involved in promoting cell proliferation, in a time and dose-dependent manner. KH-3 was also identified to induce apoptosis cell death via inhibiting the anti-apoptotic protein BCL2. The cell cycle analysis revealed that KH-3 treatment caused the S phase accumulation. Therefore, the cell proliferation inhibition by KH-3 results from a combination of apoptosis and cell cycle arrest. Furtherly, KH-3 restored the effects of docetaxel in inducing apoptotic cell death in 231-TR cells. Together, this study provides a new strategy to overcome chemotherapy resistance in TNBC cells by functional inhibiting HuR. Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu. Inhibition of RNA binding protein HuR function sensitizes the TNBC to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-08.