Neoadjuvant Treatment Regimens Research Articles

Prognostic analysis of pathological complete response after neoadjuvant therapy for locally advanced gastric cancer: A national, multicenter, retrospective study.

346 Background: Several research findings indicate that some patients with locally advanced gastric cancer (LAGC) who undergo neoadjuvant therapy followed by curative surgery can achieve pathological complete response (pCR). Whether pCR is equivalent to cure, serves as a good prognostic indicator for long-term survival, and whether patients achieving pCR require subsequent adjuvant therapy are still unknown. Therefore, we conducted a nationwide multicenter retrospective study to investigate the long-term efficacy of patients with LAGC who achieved pCR after neoadjuvant therapy. Methods: Clinical and pathological data were collected from 351 patients with locally advanced gastric cancer who achieved pCR after neoadjuvant therapy between January 2018 and October 2023 at 14 medical centers in China. These patients were matched 1:1 with non-pCR patients based on age, gender, clinical T stage, and N stage. This study evaluated general clinical data, neoadjuvant treatment regimens, cycles, surgical outcomes, and follow-up information including postoperative adjuvant therapy, recurrence, metastasis, and survival status up to November 2023. Results: Negative Serum tumor markers, non-signet ring cell carcinoma and neoadjuvant treatment regimens were closely associated with pCR. Patients achieving pCR were more likely to reach ypN0 status after neoadjuvant therapy compared to non-pCR patients. Survival analysis showed significantly higher overall survival (OS) and disease-free survival (DFS) in pCR patients compared to matched non-pCR patients. Moreover, OS and DFS were significantly higher in ypN0 patients within the pCR group compared to non-pCR patients. However, there was no significant difference in OS and DFS between ypN+ patients in the pCR group and non-pCR patients. Additionally, postoperative adjuvant chemotherapy did not significantly impact OS and DFS in the pCR group. Conclusions: pCR is an independent prognostic factor for OS and DFS. However, survival benefits from pCR are limited to patients achieving ypT0N0 status, while ypT0N+ patients do not benefit from pCR. Furthermore, adjuvant chemotherapy may not improve the prognosis of patients achieving pCR after neoadjuvant therapy.

Impact of time to surgery on outcomes in patients with advanced esophageal squamous cell carcinoma following neoadjuvant therapy: An exploratory analysis of phase III trial JCOG1109.

458 Background: JCOG1109, a multicenter three-arm phase III trial, evaluated three neoadjuvant treatment regimens for advanced esophageal squamous cell carcinoma (ESCC), cisplatin and 5-fluorouracil (CF), docetaxel, cisplatin, and 5-fluorouracil (DCF), and cisplatin, 5-fluorouracil, and radiation therapy (CF-RT). The trial demonstrated the superiority of neoadjuvant DCF therapy in improving overall survival (OS). This exploratory analysis investigates the impact of the interval time from completion of neoadjuvant therapy to surgery (time to surgery, TTS) on both short- and long-term outcomes across different neoadjuvant therapy regimens. Methods: This analysis included patients from JCOG1109 who underwent surgery after neoadjuvant therapy. Patients were categorized into four TTS subgroups within each arm, based on quartiles of the overall cohort. Short-term outcomes such as perioperative complications, as well as long-term outcomes including OS and progression-free survival (PFS) were evaluated across these TTS subgroups. Results: Of the 601 patients enrolled in JCOG1109, 546 patients proceeded to surgery following neoadjuvant therapy. The median TTS was 35 days (range: 16-81) for the CF arm, 38 days (range: 17-109) for the DCF arm, and 41 days (range: 14-98) for the CF-RT arm. Baseline characteristics were well-balanced across all TTS subgroups in each treatment arm. Short-term outcomes revealed that operative time and overall proportions of postoperative complications were comparable. However, in the CF-RT arm, a longer TTS was associated with increased blood loss (200 ml, 210 ml, 300 ml, 370 ml; p-value for trend test = 0.010) and tended to increase the risk of anastomotic leakage (6%, 7%, 14%, 18%; p-value for trend test = 0.073). No significant differences in OS or PFS were observed across TTS subgroups in any treatment arm, with hazard ratios indicating no clear trend toward improved or worsened long-term outcomes. Conclusions: The timing of surgery following neoadjuvant therapy does not appear to affect long-term prognosis in patients with advanced ESCC, irrespective of the neoadjuvant therapy regimen. However, for patients undergoing neoadjuvant CF-RT, earlier surgery may be advantageous in reducing the risk of increased surgical complexity and anastomotic leakage.

Immune microenvironment features underlying the superior efficacy of neoadjuvant immunochemotherapy over chemotherapy in local advanced gastric cancer

BackgroundThe therapeutic efficacy of neoadjuvant immunotherapy combined with chemotherapy (Io+Chemo) is superior than chemotherapy alone (Chemo). However, the mechanism of Io+Chemo superiority remains to be further elucidated.MethodsThe study included 128 patients with resectable stage II-III gastric cancer, in which 63 were given neoadjuvant Io+Chemo, and 65 Chemo alone. Patients given Io+Chemo were treated with 2-4 cycles of PD-(L)1 inhibitor (Pembrolizumab, Sintililimab or Nivolumab) with S-1 and oxaliplatin (SOX) or capecitabine and oxaliplatin (XELOX) before surgical resection. Patients given Chemo were treated with 2-4 cycles of SOX or XELOX before surgical resection. Tumor tissues were evaluated for tumor-infiltrating immune cells (TIICs) using immunohistochemistry and QuPath software quantitative analysis, for detecting T, B, NK, plasma cells, and macrophages. The relationship between TIICs and different neoadjuvant treatment regimens and pathological responses was also explored.ResultsCompared with Chemo, Io+Chemo induced higher rates of pathological complete response (33.3 vs. 9.2%, p=0.001) and major pathological response (MPR) (49.2 vs. 30.8%, p=0.033). Compared with Chemo group, density of CD4+(1904.8 vs. 1530), CD8+(1982.9 vs. 1124.4), CD20+(1115.6 vs. 574), CD38+(1580.4 vs. 1128), CD138+(1237.2 vs. 496.4), and CD56+ (596.8 vs. 159) cells was increased 24.5%, 76.4%, 94.4%, 40.1%, and 149.2% respectively, whereas CD163+ macrophages (994.4 vs. 1706) was decreased 41.7% in Io+Chemo group.ConclusionsOur study favors neoadjuvant Io+Chemo over Chemo and reveals Io+Chemo can induce the formation of an immune-activated microenvironment that make Io+Chemo superior to Chemo.

Tolerability and Preliminary Outcomes of Adjuvant T-DM1 in HER2-Positive Breast Cancer After Neoadjuvant Therapy: The ATD Study.

HER2-positive breast cancer (HER2+BC) is an aggressive subtype, with neoadjuvant treatment (NAT) aiming to achieve a pathological complete response (pCR) to improve long-term outcomes. Trastuzumab emtansine (T-DM1) has been established as the standard of care in the adjuvant setting for HER2+BC patients who do not obtain pCR. The ATD study aimed to evaluate the real-world tolerability of T-DM1 in this setting. The secondary objective was to assess the effectiveness. This was a multicenter, retrospective study across 24 Italian oncology centers, including 410 patients with HER2+BC treated with adjuvant T-DM1 following a lack of pCR after NAT. Patient characteristics, NAT regimens, and surgical outcomes were recorded. Tolerability was assessed by documenting adverse events (AEs) according to the CTCAE (v5.0). Preliminary effectiveness was evaluated in terms of relapse-free survival (RFS) and overall survival (OS). Overall, 228 patients (55.6%) experienced at least one AE related to T-DM1, with 4.9% experiencing grade 3 or higher AEs. The most common AEs were hepatotoxicity (18.5%) and thrombocytopenia (17.6%). T-DM1 was discontinued in 10.0% of patients due to toxicity. After a median follow-up of 25 months, 31 relapse events (7.6%) and 22 deaths (5.4%) were reported. The preliminary incidence of RFS and OS events was similar between patients who completed the T-DM1 course and those who discontinued it early. T-DM1 demonstrated a manageable safety profile, and the adverse events were consistent with those reported in randomized trials. The data are not yet sufficient to allow for a formal analysis of RFS and OS, and long-term follow-up is required.

Now or Later? The Role of Neoadjuvant Treatment in Advanced Endometrial Cancer: A Systematic Review.

Background: Endometrial cancer (EC) is, nowadays, the most frequent gynecological malignancy worldwide. The main treatment approach for EC is surgery, especially for early-stage tumors. For advanced EC, chemotherapy (CT) with carboplatin and paclitaxel is the standard treatment, especially for women with metastatic or recurrent disease. The present systematic review aimed to establish whether neoadjuvant treatment regimens with CT and/or radiotherapy (RT) lead to better survival outcomes compared to upfront surgery in advanced EC. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, through the string "(("Endometrial Neoplasms"[Mesh]) AND "Hysterectomy"[Mesh]) AND "Radiotherapy"[Mesh] AND Chemotherapy", the selection of articles was made. A quality assessment was conducted using the Newcastle-Ottawa Scale (NOS). The studies included patients with EC with survival and recurrence outcomes-patients treated with upfront surgery or neoadjuvant CT ± External Beam Radiation Therapy (EBRT) or CT ± Brachytherapy (BT). Results: According to the selected evidence in the scientific literature, the 5-year DFS was 21.3% for upfront surgery and ranged from 42 to 73% for neoadjuvant chemotherapy. Also, the 5-year OS was 6.2 to 49.7% with upfront surgery and 15.5 to 100% for neoadjuvant schemes. None of the studies dedicated to surgery reported the 5-year Recurrence Rate (RR), while in the neoadjuvant treatments, it ranged from 27 to 64.7%. Conclusions: The literature's paucity of data makes it difficult to compare neoadjuvant therapy regimens with upfront surgery in advanced endometrial carcinoma. Nevertheless, the current data show more encouraging results for the neoadjuvant treatment group.

L’immunothérapie péri-opératoire des cancers bronchiques non à petites cellules (CBNPC) : standards actuels et perspectives

Surgery is the cornerstone of the treatment for stage I to IIIA NSCLC. Perioperative platinum-based chemotherapy has long been combined with surgery for patients with resectable stage II-IIIA disease, although the benefits are modest, with an increase in overall survival of approximately 5 %. Recently, immunotherapy has been integrated into neo-adjuvant, adjuvant, and perioperative treatment regimens based on data demonstrating improved event-free survival (EFS) and disease-free survival (DFS), respectively, for localized or locally advanced resectable NSCLC, without activating mutation. Two phase 3 trials have shown an adjuvant benefit and have been approved in Europe but are not supported in France. Four phase III trials Checkmate-816, Checkmate-77T, AEGEAN and KEYNOTE-671 showed a benefit from the combination of an immune checkpoint inhibitor with chemotherapy in the neoadjuvant or in perioperative setting. The results of Checkmate-816 enabled the early access authorization of Nivolumab, in combination with platinum-based chemotherapy in the neoadjuvant treatment of adult patients with resectable NSCLC at high risk of recurrence, including tumors express PD-L1 at the threshold ≥ 1 %, not EGFR mutated, nor ALK translocated.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Mapping of lymph node metastasis from esophageal squamous cell carcinoma after neoadjuvant treatment: a prospective analysis from a high-volume institution in China.

The study aimed to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. A two-field lymphadenectomy was routinely performed, and an extensive three-field lymphadenectomy was performed if cervical lymph node metastasis was suspected. According to AJCC/UICC 8, lymph node stations were investigated separately. The number of patients with metastatic lymph nodes divided by those who underwent lymph node dissection at that station was used to define the percentage of patients with lymph node metastases. Data are also separately analyzed according to the pathological response of the primary tumor, neoadjuvant treatment regimens, pretreatment tumor length, and tumor location. Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled. Lymph node metastases were found in 212 patients (34.0%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587), and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length of >4cm and non-pathological complete response of the primary tumor, the metastatic rate of the right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively. For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most commonly seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285), and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in the paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252). The study precisely determined the distribution of lymph node metastases in ESCC after neoadjuvant treatment, which may help to optimize the extent of lymphadenectomy in the surgical management of ESCC patients after neoadjuvant therapy.

An analysis of PIK3CA hotspot mutations and response to neoadjuvant therapy in breast cancer patients from four prospective clinical trials.

The PI3K signaling pathway is frequently dysregulated in breast cancer (BC), and mutations in PIK3CA, are relevant for therapy resistance in HER2pos BC. Mutations in exons 9 or exon 20 may have different impact on response to neoadjuvant chemotherapy-based treatment regimens. We investigated PIK3CA mutations in 1691 early BC patients, randomized in four neoadjuvant multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880) and GeparSepto (NCT01583426). The role of different PIK3CA exons and hotspots for pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) and patient survival was evaluated for distinct molecular subgroups and anti-HER2 treatment procedures. A total of 302 patients (17.9%) of the full cohort of 1691 patients had a tumor with a PIK3CA mutation, with a different prevalence in molecular subgroups: luminal/HER2neg 95 of 404 patients (23.5%), HER2pos 170 of 819 patients (20.8%) and TNBC 37 of 431 patients (7.9%). We identified mutations in PIK3CA exon 20 to be linked with worse response to anti-HER2 treatment (OR=0.507, 95%CI 0.320-0.802, p=0.004), especially in HR positive HER2 positive BC (OR=0.445, 95%CI 0.237-0.837, p=0.012). In contrast, exon 9 hotspot mutations p.E452K and p.E545K revealed no noteworthy differences in response therapy response. Luminal/HER2neg patients show a trend to have worse treatment response when PIK3CA was mutated. Interestingly, patients with residual disease after neoadjuvant treatment, have better survival when PIK3CA was mutated. PIK3CA hotspot mutation p.H1047R are associated with worse pCR rates after NACT in HER2pos BC, while hotspot mutations in exon 9 seems to have less impact.

A propensity-matched cohort study of neoadjuvant immunotherapy combined with chemotherapy versus neoadjuvant chemotherapy for early-stage triple-negative breast cancer.

e13134 Background: Preferred neoadjuvant treatment (NAT) regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. This study compared the efficacy, safety and biomarker exploration of camrelizumab combined with chemotherapy and chemotherapy as neoadjuvant treatment for early-stage TNBC. Methods: This study included 2 cohorts with different NAT regimens, matched (2:1) according to age, clinical T and N stage, and Ki-67 status. Patients in the immune combination chemotherapy (NIC) cohort were recruited from a phase II clinical trial (NCT04676997). NIC patients received intravenous camrelizumab at a dose of 200mg and simultaneous chemotherapy consisted of platinum-free drugs, or platinum containing drugs. Patients in the neoadjuvant chemotherapy (NAC) cohort regimen comprised 4 cycles of paclitaxel 175 mg/m2, and 4 cycles of epirubicin (90 mg/m2, d1, q2w) + cyclophosphamide (600 mg/m2, d1, q2w). The indicators of this study include pCR, breast pCR (bpCR), axillary lymph node dissection (ALND) rate, breast conserving surgery (BCS) rate and tumor immune microenvironment (TIME) analysis of gene expression profiling. Results: Of 252 eligible patients, 162 patients were identified in the analysis after propensity score matching (PSM). Compared with NAC alone, the addition of camrelizumab brought higher pCR rates (64.81% versus 37.04%, p<0.05), ALND rates (38.89% versus 12.96%, p<0.05) and comparable BCS rates (20.37% versus 15.74%, p<0.05). Gene expression analysis was performed on tumor tissue samples from 12 patients receiving NAC and 16 patients receiving NIC before and after NAT. The results showed that the TIME status of the NIC and NAC groups before treatment was basically the same. Moreover, we respectively compared the TIME status of patients with pCR and non_pCR in NIC and NAC before NAT. The results found that there were 9 significantly different signatures (p<0.05) between pCR and non_pCR patients in the NIC group, and 1 signature (p<0.05) in the NAC group, respectively. Notably, we found 8 signatures (B Cells, CD8 T Cells, TIS, IFN Gamma, Lymphoid, T Cell, APM, Immunoproteasome), that were scored significantly higher only in pCR patients in the NIC group compared with non-pCR patients, and 8 signatures could promote response to immunotherapy. The common difference signature between the two groups is Treg cells. Conclusions: In patients with early-stage TNBC, neoadjuvant treatment with camrelizumab plus chemotherapy significantly improved pCR with an acceptable safety profile. Differences in TIME may affect response to treatment regimens. Future validation in prospective randomized controlled trials with larger sample sizes is needed. Clinical trial information: NCT04676997 .

NeoTRACT: Phase II trial of neoadjuvant tumor infiltrating lymphocyte- and response-adapted chemoimmunotherapy for triple-negative breast cancer (TNBC).

TPS629 Background: Neoadjuvant chemoimmunotherapy is recommended for patients with high risk early stage TNBC. The 5 drug KEYNOTE-522 neoadjuvant chemoimmunotherapy regimen involves 5-6 months of treatment and is associated with suboptimal treatment completion due to toxicity. Approaches to deescalate chemoimmunotherapy without compromising outcomes for patients with highly chemosensitive disease are needed. Stromal tumor infiltrating lymphocyte (sTIL) enrichment is positively associated with pathologic complete response (pCR) in TNBC and may be useful to identify patients for whom de-escalation of neoadjuvant chemoimmunotherapy might be acceptable. NeoTRACT trial investigates deescalating neoadjuvant chemoimmunotherapy based on degree of pretreatment sTIL enrichment. We hypothesize that baseline immune upregulation assessed by sTILs can guide neoadjuvant treatment optimization in TNBC patients. Specifically, in patients with immune enriched TNBC (sTILs ≥30%), short anthracycline free taxane–platinum chemoimmunotherapy will yield high pCR rate. Methods: NeoTRACT is an ongoing open label phase II trial for patients with previously untreated TNM stage I (T>1cm)–III TNBC. TNBC is defined as estrogen and progesterone receptor ≤10% and HER2 negative per ASCO/CAP criteria. Patients with T4 or N3 breast cancer are excluded. Patients must have adequate organ function and no contraindication to pembrolizumab. All participants initiate carboplatin (AUC 6) + docetaxel (75mg/m2) + pembrolizumab (200mg) (CbD+P) every 21 days. After registration, sTILs are evaluated centrally on pretreatment H&E core needle biopsy slide using standard criteria. Participants are assigned to three neoadjuvant treatment regimens (A, B, or C) based on sTIL enrichment. Regimen A (sTILs ≥30%) includes four cycles CbD+P. All participants assigned to regimen A undergo breast MRI after four cycles: those with complete MRI response proceed to breast surgery; those with less than complete MRI response receive two additional cycles of CbD+P. Regimen B (sTILs 5-29%) includes six cycles of CbD+P. Regimen C (sTILs <5%) includes four cycles of CbD+P followed by four cycles of doxorubicin (60mg/m2) + cyclophosphamide (600mg/m2) + P (200mg) (AC+P). All patients undergo surgery after completing the assigned neoadjuvant regimen. Breast/axillary surgery, adjuvant systemic therapy, and radiotherapy are recommended per standard of care. pCR is defined as absence of residual invasive disease in breast and axilla. Primary endpoint is pCR rate among participants with ≥30% sTILs. Secondary endpoints include residual cancer burden (RCB) rates in patients with ≥30% sTILs, pCR and RCB rates in patients with 5-29% and <5% sTILs, and event free and overall survival for all patients. As of January 2024, 45 of 139 participants have been enrolled. Clinical trial information: NCT05645380 .

Influence of neoadjuvant regimen on the prognosis of locally advanced gastric and gastroesophageal junction cancer with HER2 overexpression.

e16082 Background: The relative high recurrence rate in locally advanced gastric or gastroesophageal junction (G/GEJ) cancer with Her2 overexpression after surgery, along with the absence of a standard neoadjuvant treatment protocol, necessitates exploration of novel approaches for this patient population. Methods: In this study, we conducted a retrospective analysis of clinical characteristics, postoperative pathological results, and survival data for patients who underwent neoadjuvant treatment and subsequent surgery at our center from September 2020 to December 31, 2022. The inclusion criteria were as follows: 1) pathologically confirmed adenocarcinoma of the G/GEJ; 2) diagnosed as cT3-4 or N+ by enhanced CT and endoscopic ultrasound; 3) Her2 immunohistochemistry 3+ or 2+ with Fish positive in biopsy specimens; 4) discussed in a multidisciplinary team for the need for neoadjuvant treatment; 5) received 2-4 cycles of neoadjuvant therapy; 6) underwent radical D2 surgery; 7) had complete follow-up data. Results: Seventy-three patients met the inclusion criteria, with 19 receiving chemotherapy + anti-PD-1, 10 receiving chemotherapy + anti-Her2, and 44 receiving chemotherapy alone. Their pCR rates were 31.6%, 10%, and 2.3%, respectively (P = 0.003); MPR rates were 42.1%, 30%, and 11.4% (P = 0.022). As of the last follow-up on December 31, 2023, the median DFS for the chemotherapy group was 18.1 months (95% confidence interval 14.9-21.3); median DFS for the other two groups had not been reached. DFS analysis revealed differences in median DFS among different neoadjuvant treatment regimens (P = 0.025); further pairwise comparisons indicated that this difference mainly stemmed from the chemotherapy + anti-Her2 group compared to the chemotherapy group. Conclusions: In locally advanced gastric and gastroesophageal junction cancer with Her2 overexpression, neoadjuvant chemotherapy combined with anti-Her2 treatment improves the pCR rate and prolongs DFS compared to neoadjuvant chemotherapy alone.

Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.

e12634 Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .

Efficacy and safety of neoadjuvant chemoradiotherapy combined with tislelizumab and thymalfasin in the treatment of locally advanced lower rectal cancer.

e15612 Background: Thymalfasin, as an immunomodulator, can enhance the anti-tumor effects of T cells, NK cells, and macrophages. This study explored the efficacy and safety of a new adjuvant treatment regimen for rectal cancer, combining thymalfasin with chemoradiotherapy and the PD-1 inhibitor tislelizumab, and its impact on the immune microenvironment. Methods: This retrospective study enrolled 26 patients with locally advanced rectal cancer from March 2021 to December 2022. Thirteen patients received long-course concurrent chemoradiotherapy combined with concurrent tislelizumab treatment, and thirteen received thymalfasin combined with long-course chemoradiotherapy and concurrent tislelizumab treatment (radiotherapy: 50 Gy/25 f; capecitabine, 1000mg/m2, bid; tislelizumab: 200mg, every 21 days, 3 cycles; Thymalfasin: 1.6mg, biw). The postoperative pathological complete response rate (ypT0N0M0), tumor regression grade (AJCC 8th Version), and adverse event (CTCAE 4.0) incidence were assessed, along with changes in the immune microenvironment before and after treatment using multiplex immunofluorescence staining. Results: The pathological complete response rates observed postoperatively were 61.5% in the treatment group, compared to 38.5% in the control group. The distribution of tumor regression grades 0, 1, 2, and 3 was 69.2%, 15.4%, 15.4%, 0% in the treatment group respectively, and 38.5%, 38.5%, 7.7%, 15.4%, in the control group respectively. The adverse event rates reached 84.6% in the treatment group and 76.9% in the control group, with all events classified as either grade 1 or 2 according to the CTCAE 4.0. Significant reductions in CD4+PD1+ cell density (p < 0.001), CD8+PD1+ cell density (p = 0.024), CD68+ cell density (p = 0.007), the CD4/CD8 ratio (p < 0.001), and the CD68+CD86+/CD68+CD163+ ratio (p = 0.012) were demonstrated through multiplex immunofluorescence following neoadjuvant treatment. The treatment group exhibited significant decreases in CD8+PD1+ cell density (p = 0.025) and CD68+CD163+ cell density (p = 0.021) when compared to the control group. Conclusions: Thymalfasin combined with chemoradiotherapy and tislelizumab as a neoadjuvant treatment regimen for patients with locally advanced lower rectal cancer has shown favorable efficacy and safety. Neoadjuvant chemoradiotherapy combined with immunotherapy restored T cell function and reduced the proportion of tumor-associated macrophages, but macrophages polarized towards an M2-like phenotype. Thymalfasin may play a role by synergizing with the PD-1 inhibitor to restore cytotoxic T cell function and block macrophage polarization towards M2 cells. Clinical trial information: NCT06024356 .

Characteristics and survival associated with pathological complete response following neoadjuvant treatment of locally advanced gastric cancer: a multicenter analysis in a real-world setting

Background : Neoadjuvant treatment (NAT) has become the standard treatment for locally advanced gastric cancer (LAGC). A small number of patients could achieve pathological complete response (pCR) after NAT. This study was performed to determine the factors predicting pCR and recurrence, and to investigate the pattern of recurrence in patients with pCR after NAT followed by surgery. Methods : We collected 488 LAGC patients who underwent surgery in three hospitals between September 2015 and October 2022. The primary endpoint was overall survival (OS) and recurrence-free survival (RFS). Logistic regression analyses were performed to identify independent variables associated with pCR and the nomogram was created. Result : 80 (16.4%) patients were found with pCR and had significantly better OS and RFS than non-pCR group. The recurrence rates in the pCR and non-pCR groups were 7.5% (6 of 80) and 40.2% (164 of 408) respectively. However, the recurrence time and location had no significant difference between these two groups. Interestingly, all the 6 pCR patients who had recurrences received adjuvant therapy. Chemotherapy plus immunotherapy as NAT could significantly increase the pCR rate and prolong RFS than chemotherapy alone. Both OS and RFS were not significantly different between all patients who received adjuvant chemotherapy and observation only. Histological type and NAT regimen were independent factors to predict pCR in the nomogram.

Abstract PO1-01-02: Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study

Abstract Background: The optimal neoadjuvant treatment regimen for HER2-positive breast cancer remains unclear, especially regarding the use of anthracycline. We conducted a prospective phase II study to evaluate sequential neoadjuvant chemotherapy with pegylated liposomal doxorubicin (PLD)/cyclophosphamide followed by taxanes in the presence of full-course trastuzumab/pertuzumab in HER2-positive early breast cancer patients. Methods: In this single-arm, open-label, multicenter, phase II study, eligible patients with confirmed HER2-positive early breast cancer were recruited from four independent hospitals. Patients received four cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (ypT0/is ypN0, tpCR). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, the proportion of patients requiring breast-conserving surgery, and safety. For biomarkers analysis, tumor tissues were collected at baseline and evaluated for Topoisomerase 2 Alpha (TOP2A) expression assessed prospectively with immunohistochemistry (IHC) assay by independent pathologists. Results: Between May 27, 2020 and May 11, 2022, 78 eligible patients were treated and underwent surgery, of whom 42 (53.8%) patients underwent breast-conserving surgery. After neoadjuvant therapy, 47 (60.3%, 95% CI, 48.5%-71.2%) patients achieved a tpCR in the breast and axilla. The bpCR was observed in 49 (62.8%) patients. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. All (100%) patients achieved disease control since the end of the first cycle. No correlations between clinicopathological variables and pathological response were observed. Grade 3 or worse AEs occurred in 35 (44.9%) patients. Nine (11.5%) patients experienced asymptomatic LVEF reduction (≥10% from baseline), but all with a minimum value of >55%. No treatment-related surgical delay or death occurred. For biomarkers analysis, the status of TOP2A was not found to be associated with pCR or 4th-cycle ORR. Conclusions: This dual HER2-blockade plus polychemotherapy as sequential neoadjuvant regimen demonstrates promising anti-tumor activity and acceptable tolerability for patients with HER2-positive breast cancer. Citation Format: Yaping Yang, Liang Jin, Yudong li, Fengxia Gan, Nanyan Rao, Jun Zhang, Ruifa Feng, Zhenzhen Liu, Qiang Liu. Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study [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 PO1-01-02.

Abstract PO1-01-04: The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [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 PO1-01-04.

Current Immunotherapy Treatments of Primary Breast Cancer Subtypes.

Breast cancer receives the most funding when compared to any other cancer type, according to a global study conducted by The Lancet. Nevertheless, this malignancy remains the most diagnosed cancer among women and relies heavily on a neoadjuvant treatment regimen of chemotherapy and targeted therapy. After standard treatment, 25-30% of breast cancer patients still develop disease recurrence and must undergo cytoreductive debulking surgery followed by intensive chemotherapy. An array of targeted therapies are currently being utilized and developed to alleviate negative side effects, eradicate cancer growth, and diminish disease recurrence. Immunotherapy is a promising cancer therapy that upregulates one's immune system to stimulate a therapeutic effect and is utilized for cancer management among other ailments such as immunodeficiencies, hypersensitivity reactions, autoimmune diseases, inflammatory disorders, tissue and organ transplantation, and infectious diseases. This review highlights the five primary subtypes of breast cancer, provides a brief history of immunotherapy, evaluates the current landscape of treating breast cancer with immunotherapy, analyzes selected ongoing or recently completed immunotherapy clinical trials for hormone receptor-positive, HER2-enriched, and triple-negative breast cancer, and examines future trends for the treatment of breast cancer with immunotherapeutic techniques. This review provides a formal summary categorized by breast cancer subtype rather than types of immunotherapeutic treatment.

Results of a Randomized Clinical Study of Gemcitabine Plus Nab-Paclitaxel Versus Gemcitabine Plus S-1 as Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma (RCT, CSGO-HBP-015)

BackgroundThe optimal neoadjuvant chemotherapy (NAC) regimen for patients with localized pancreatic ductal adenocarcinoma (PDAC) remains uncertain. This trial aimed to evaluate the efficacy and safety of two neoadjuvant chemotherapy (NAC) regimens, gemcitabine plus nab-paclitaxel (GA) and gemcitabine plus S-1 (GS), in patients with resectable/borderline-resectable (R/BR) PDAC.Patients and MethodsTreatment-naïve patients with R/BR-PDAC were enrolled and randomly allocated. They received two cycles (2 months) of each standard protocol, followed by radical surgery for those without tumor progression in general hospitals belonging to our intergroup. The primary endpoint was to determine the superior regimen on the basis of achieving a 10% increase in the rate of patients with progression-free survival (PFS) at 2 years from allocation.ResultsA total of 100 patients were enrolled, with 94 patients randomly assigned to the GS arm (N = 46) or GA arm (N = 48). The 2-year PFS rates did not show the stipulated difference [GA, 31% (24–38%)/GS, 26% (18–33%)], but the Kaplan–Myer analysis showed significance (median PFS, GA/GS 14 months/9 months, P = 0.048; HR 0.71). Secondary endpoint comparisons yielded the following results (GA/GS arm, P-value): rates of severe adverse events during NAC, 73%/78%, P = 0.55; completion rates of the stipulated NAC, 92%/83%, P = 0.71; resection rates, 85%/72%, P = 0.10; average tumor marker (CA19-9) reduction rates, −50%/−21%, P = 0.01; average numbers of lymph node metastasis, 1.7/3.2, P = 0.04; and median overall survival times, 42/22 months, P = 0.26.ConclusionsThis study found that GA and GS are viable neoadjuvant treatment regimens in R/BR-PDAC. Although the GA group exhibited a favorable PFS outcome, the primary endpoint was not achieved.

Abstract 2582: Intra- and peri-tumoral radiomic features are predictive of pathologic response to multiple neoadjuvant therapy regimen in rectal cancers via pre-treatment MRI

Abstract Introduction: Rectal cancers undergo neoadjuvant chemoradiation prior to resection, with increasing evidence that neoadjuvant chemotherapy or immunotherapy can boost clinical or pathologic response rates. However, baseline clinical tumor staging and carcinoembryonic antigen levels are limited for identifying which patients will most benefit from a multimodal neoadjuvant regimen, and which will not. We evaluated whether radiomics (computational features from radiographic images) from pretreatment MRI could identify which rectal cancer patients will achieve clinical or pathologic response to different neoadjuvant treatment regimens. Methods: MRI scans were retrospectively obtained from 3 different institutions for rectal cancer patients who had either undergone neoadjuvant chemoradiation or an experimental immunotherapy + chemoradiation. After pre-processing all MRI scans, tumor was manually delineated with an automated annotation of a 10 mm peritumor region. 916 radiomic features were extracted from two planes of acquisition (axial, coronal) and two ROIs (tumor, peritumor). 5 top-ranked radiomic features were identified from each region and plane via multi-stage mutual information feature selection to train a linear discriminant machine classifier to assign a predicted likelihood of achieving complete response to each patient. Model performance was validated via ROC analysis against response groups defined via (i) tumor regression grade indicating no tumor present on surgical pathology, and (ii) 1-year clinical complete response for patients who underwent non-operative management. Clinical variables (CEA, clinical stage) were statistically compared between response groups. Results: Training cohort comprised 64 patients who underwent chemoradiation alone (2 institutions, median age 61 yrs, M:F:MtF = 36:27:1). Validation cohort included 37 patients who underwent experimental TGFß inhibitor therapy prior to chemotherapy + chemoradiation (1 institution, median age 51 yrs, M:F = 25:12). Area under the ROC curve for multi-plane tumor+peritumor radiomic features (0.765 ± 0.054) was significantly higher for distinguishing complete response vs non/partial response compared to tumor (AUC = 0.635 ± 0.057, p < 0.0001) or peritumor (AUC = 0.612 ± 0.064, p < 0.0001). In holdout validation, performance was maintained with AUCs of 0.742 (tumor) 0.596 (peritumor), and 0.700 (all), respectively. Baseline CEA levels (p=0.3385) and cT stage (p=0.3386) were found to lack statistical significance as a predictor of response. Conclusion: Radiomic features from tumor and peritumor regions on pre-treatment MRI scans in rectal cancer patients may enable robust and accurate identification of pathologic or near-complete response after multiple neoadjuvant treatment regimen, while outperforming baseline clinical variables. Citation Format: Leo Bao, Thomas DeSilvio, Benjamin N. Parker, Mohsen Hariri, Prathyush Chirra, Murad Labbad, Stephen Tang, Gregory M. O'Connor, Emily Steinhagen, Jennifer L. Miller-Ocuin, Amit Gupta, Eric L. Marderstein, Aaron Carroll, Marka Crittenden, Michael J. Gough, Smitha Krishnamurthi, Kristina H. Young, Satish E. Viswanath. Intra- and peri-tumoral radiomic features are predictive of pathologic response to multiple neoadjuvant therapy regimen in rectal cancers via pre-treatment MRI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2582.

Real-World Neoadjuvant Treatment Patterns and Outcomes in Resected Non–Small-Cell Lung Cancer

BackgroundNovel neoadjuvant chemoimmunotherapy treatments are being investigated for locally advanced non–small-cell lung cancer (NSCLC), but real-world outcomes for neoadjuvant treatments are poorly understood. This study examined neoadjuvant treatment patterns, real-world event-free survival (rwEFS) and overall survival (OS) in patients with resected, stage II-III NSCLC in the United States (US). MethodsThis retrospective study identified patients in the SEER–Medicare database (2007-2019) with newly diagnosed stage II, IIIA, and IIIB (N2) NSCLC (AJCC 8th edition) treated with neoadjuvant chemo/chemoradiotherapy and resection (index date: neoadjuvant therapy initiation). Neoadjuvant treatment regimens were described. rwEFS (time from index to first recurrence or death, whichever occurred first) and OS (time from index to death) were summarized by Kaplan–Meier analysis for overall population, by disease stage at diagnosis, and by neoadjuvant treatment modality. Results221 patients (stage II, N=70; stage III, N=151) met eligibility criteria. The median follow-up from index was 32.7 months. All patients received neoadjuvant chemotherapy (51%) or chemoradiotherapy (49%) prior to surgery; 97% of patients received platinum-based regimens, among which carboplatin+paclitaxel was the most frequent (45%). In all patients, median rwEFS was 17.6 months and 5-year rwEFS was 20.9%; median OS was 48.5 months and 5-year OS was 44.9%. 71% of patients had disease recurrence during follow-up; among them, 28% developed locoregional recurrence as the first recurrence event. ConclusionsPatients with resected, stage II-III NSCLC who received neoadjuvant chemo/chemoradiotherapy have high rates of disease recurrence and poor survival outcomes, highlighting need for more effective treatments to improve survival rates.