Non-visceral Metastases Research Articles

The prognostic significance of FOXP3 expression in patients with metastatic HER2-positive breast cancer

Background. The effectiveness of targeted therapy in patients with HER2+ breast cancer largely depends on the tumor microenvironment. Regulatory T-lymphocytes (FOXP3+) negatively regulate immune responses and are mostly considered a factor of unfavorable prognosis. Breast cancer is a heterogeneous disease with unique biological properties for each molecular subtype. The impact of regulatory T cells on the prognosis of HER2+ breast cancer is controversial. Purpose – to evaluate the prognostic significance of regulatory T cells in patients with metastatic HER2+ breast cancer. Materials and Methods. The study included 78 patients with HER2+ breast cancer who were treated at the Sumy Regional Clinical Oncology Center from 2014 to 2024. Data on clinical and pathological characteristics of patients were taken from the primary medical documentation. Immunohistochemistry was performed for all samples of tumor tissue. Regulatory T lymphocytes were visualized using antibodies against FOXP3. Pearson test, One-way ANOVA, Kaplan–Meier method, and logarithmic test were used for statistical analysis. The Local Ethics Committee of the Sumy Regional Clinical Oncology Center approved the study. Results. The mean age of patients with low and high Foxp3 expression was 53.1 ± 1.74 and 57.3 ± 1.64, respectively. Among patients with high Foxp3 expression, there was a high proportion of women younger than 50 years (p = 0.0423) and estrogen-negative breast cancer (χ2 = 8.4080, p = 0.023). Other clinicopathological characteristics of the patients, such as the location of the primary tumor, histopathological diagnosis, the tumor grades, visceral and non-visceral metastases, and the Ki67 proliferation index, did not show an association with Foxp3 expression. Median progression-free survival was 12.9 months and 15.5 months for patients with low and high Foxp3 expression, respectively (Log-rank p = 0,0001). Median overall survival was 21.6 months and 46.9 months for patients with low and high Foxp3 expression, respectively (Log-rank p = 0,0001). Conclusions. In patients with metastatic HER2+ breast cancer, high Foxp3 expression is associated with better progression-free and overall survival. Among those with high FOXP3 expression, women under 50 years and with estrogen-negative breast cancer are more prevalent.

Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in patients (pts) with low tumor burden.

4566 Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC that had not progressed with 1L platinum-based chemotherapy (PBC). Results led to the incorporation of avelumab 1LM into international guidelines. Prior analyses have shown that low tumor burden (eg, nonvisceral metastases or lymph node [LN]-only disease) is associated with better outcomes in pts with aUC receiving immune checkpoint inhibitors. We report post hoc analyses of efficacy and safety in subsets of pts with low tumor burden from JAVELIN Bladder 100. Methods: Eligible pts with unresectable locally advanced (LA) or metastatic UC without progression after 1L PBC were randomized 1:1 to receive avelumab + BSC (n=350) or BSC alone (n=350). The primary endpoint was OS measured from randomization; secondary endpoints included PFS and safety. In this post hoc analysis, pts with nonvisceral metastases included those with LA disease or only nonvisceral disease, including bone metastasis, at randomization. Results: In the avelumab + BSC and BSC alone arms, 159 and 159 pts had nonvisceral metastases and 51 and 51 pts had LN-only disease, of whom 42 and 35 pts had LN-only disease in the pelvic/retroperitoneal area. At the efficacy data cutoff (June 4, 2021), median follow-up was ≥38 mo in both arms (≥2 y in all pts). In all subgroups, OS and PFS were prolonged with avelumab + BSC vs BSC alone (Table). Incidence of treatment-related adverse events (TRAEs) with avelumab were similar across subgroups. In the avelumab + BSC and BSC alone arms, subsequent anticancer drug treatment was received by 90 (56.6%) vs 119 pts (74.8%) with nonvisceral metastases, 27 (52.9%) vs 39 pts (76.5%) with LN-only disease, and 22 (52.4%) vs 27 pts (77.1%) with pelvic/retroperitoneal LN-only disease. Conclusions: Exploratory analyses suggest that avelumab 1LM has pronounced efficacy and manageable toxicity in pts with aUC who have low tumor burden, supporting its use as a standard of care in this setting. Clinical trial information: NCT02603432 . [Table: see text]

Abstract PO1-16-02: Correlation of Circulating Tumor Cells (CTC) with Clinical Characteristics, Pathological Factors, and Treatment Response in Patients with Metastatic Breast Cancer (MBC)

Abstract Background: Circulating Tumor Cells (CTC) can be isolated in 40-80% of patients with metastatic breast cancer (MBC). High levels of CTC, defined as ≥5/7.5 ml of blood are associated with shorter progression-free survival and overall survival. CTC can be tested for clinically relevant biomarkers, such as ER, and HER2 status, and have the potential to guide therapy as well as help with disease monitoring. We investigated CTC detection rate, its correlation with clinical characteristics, pathological characteristics, and response to treatment in patients with any type of metastatic breast cancer who progressed on at least one line of therapy. Methods: Eligible patients with MBC were enrolled in the IMAGE-II study (Individualized Molecular Analyses Guide Efforts in Breast Cancer) NCT02965755, in which we obtained archival tissue as part of the standard of care, and prospectively collected serial blood samples for CTC analysis. We compared CTC levels and biomarker status with clinical factors, tissue-based pathology, and molecular biomarkers. We assessed whether changes in CTC count correlated with treatment response. Blood samples were collected at baseline (Day 1), after 1-2 weeks of therapy, after 8-12 weeks, and at subsequent restaging (every 8-12 weeks). Medical records were reviewed every 3 months for ongoing treatment response, and death. Samples were processed at the Biocept CLIA-certified Laboratory. CTC were enumerated by the presence of CD45- and DAPI+ cells. Further CTC characterization was performed by antibody staining of specific protein biomarkers (ER, HER2). Fisher’s exact test was used to evaluate the association between baseline CTC < 5 and ≥5/7.5ml with patient characteristics. McNemar’s test was used to assess discordance between tissue-based and CTC-defined markers. Results: Between 1/26/2018 and 12/31/22 baseline samples were collected from 70 women with a median age of 56 (36-82) who were enrolled at four study sites. CTC was detected in 59 (84%) of participants. Baseline CTC counts were < 5/7.5 ml in 37/59 (63%) and ≥5/7.5 ml in 22/59 (37%) of participants. Differences between breast cancer subtype and CTC-receptor status were observed (Table 1). Among the 41 patients who were ER-positive, 31 (76%) were CTC ER-negative(p< 0.001). Among 29 patients who were ER-negative, 4 (14%) were CTC ER-Positive (P< 0.001). Among the 7 patients who were HER2 positive, 2(29%) were HER2 positive on CTC. Among 63 patients who were HER2 negative, 7(11%) had HER2 expression on their CTC. The discordance in the classification of HER2 wasn't statistically significant (p=0.77). Elevated CTC at baseline was more frequently detected in younger participants (< 50 years old) (55% vs 27%; P=0.22), in Black women compared to White (60 % vs 29 %, P=0.27), and in participants with visceral vs non-visceral metastasis (52% vs 28 %, P=0.40). Patients with CTC ≥5 vs < 5/7.5mL at baseline had a shorter duration of anti-HER2-based therapy (61.5 vs 836 days, p=0.04). There were no statistically significant differences among participants who received chemotherapy agents (316.5 vs 365.5 days, P=0.88), endocrine therapy (376 vs 490 days, P=0.89), or overall therapy (272 vs 390 days, P=0.21). Conclusions: We observed significant differences in the expression of ER between tumor tissue and CTC, which can be partly due to tumor evolution over time. Additionally, participants who are young, Black, and those who have visceral metastasis may have higher CTC counts. Higher CTC counts were associated with a shorter duration of anti-HER2 therapy. Although it didn’t meet statistical significance, a similar trend was observed in patients who received chemotherapy and endocrine therapy. Table 1: MBC Tissue-Based Subtype and CTC-receptor status at baseline Citation Format: Asnakech Bayable, Tingchang Wang, Amanda Blackford, Jessica Tao, Jenna Canzoniero, Seoho Lee, Faith Too, Barbara Blouw, Mary Wilkinson, Rima Couzi, Antonio Wolff, Christie Hiton, Ben Park, Vered Stearns, Cesar Santa-Maria. Correlation of Circulating Tumor Cells (CTC) with Clinical Characteristics, Pathological Factors, and Treatment Response in Patients with Metastatic Breast Cancer (MBC) [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 PO1-16-02.

PD-L1 expression and microsatellite instability (MSI) in cancer of unknown primary site.

Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features. The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.

GCISAVE: A non-comparative randomized phase II study of combination of gemcitabine cisplatin (GCis) +/- avelumab (A) in 1st line treatment for locally advanced or metastatic urothelial bladder carcinoma (MUBC)—GETUG AFU V07.

GCISAVE: A non-comparative randomized phase II study of combination of gemcitabine cisplatin (GCis) +/- avelumab (A) in 1st line treatment for locally advanced or metastatic urothelial bladder carcinoma (MUBC)—GETUG AFU V07.

Metastatic patterns and outcomes by HER2 and hormone receptor (HR) status in patients (pts) with metastatic breast cancer (mBC).

1031 Background: HER2-low status in mBC is predictive of benefit to trastuzumab deruxutan, but whether it is biologically distinct from HER2-neg disease is unclear. To better understand the prognostic significance of HER2-low status, we assessed patterns of metastases and real world overall survival (rwOS) by HER2 and HR status. Methods: Pts with mBC diagnosis from 1/1/2011 to 5/31/2022 were selected from the nationwide deidentified Flatiron Health electronic health record (EHR)-derived database. HER2 and HR status was derived from human abstraction (IHC 0-1+/2+/3+, FISH pos/neg, ER/PR) and machine learning-extraction (to classify IHC 0/1+). HER2 and HR tests prior and up to 60 days after metastatic diagnosis date (met Dx date) were included, results closest to met Dx date were used. Sites of metastasis (SOM) were grouped into mutually exclusive groups: brain, non-visceral (bone, skin, lymph node) and visceral (liver, lung, etc). Metastatic patterns stratified by HR/HER2 status were compared using chi-square tests. The association between HER2 status and rwOS, stratified by HR status, was evaluated using Cox models adjusted for age, race/ethnicity, practice, SOM, SES, and stage. rwOS stratified by HR/HER2 status and SOM were estimated via KM analysis. Results: Among 22,932 pts with mBC, HER2-low prevalence was 49%. HER2-low mBC was more likely to be HR+ than HER2-neg or HER2+ (84%, vs 70% and 65%; p&lt;0.01). Pts with HER2-low and HER2-neg mBC had similar SOM overall, distinct from HER2+. For example, among HR+ pts, HER2-low and HER2-neg pts were less likely than HER2+ pts to have brain (4% and 4% vs 10%; p&lt;0.01) or visceral metastases (51%, 50% vs 58%; p&lt;0.01) but more likely to have non-visceral metastases (45% and 46% vs 32%; p&lt;0.01). Compared to HER2-low pts, HER2-neg pts had similar rwOS if HR+ (hazard ratio 1.02, 95% CI 0.98-1.08) and slightly worse if HR-neg (hazard ratio 1.18, 95% CI 1.03-1.21). rwOS varied by HR/HER2 status and SOM. Conclusions: Our findings indicate that HER2-low mBC has biologic similarities to HER2-neg mBC. While slight differences were observed between HER2-neg and HER2-low pts in the HR-neg subgroup, overall rwOS differences were associated more strongly with HER2+ status, HR+ status, and metastatic pattern, indicating that HER2-low status may be more informative as a predictive rather than a prognostic biomarker. [Table: see text]

Prognostic biomarkers and clinical outcomes in neuroendocrine prostate cancer (NEPC).

209 Background: NEPC includes both pure small cell carcinoma and mixed tumors with varying degrees of adenocarcinoma and neuroendocrine histology. It arises de novo or is treatment associated (TA) post androgen deprivation therapy. Clinical outcome data and prognostic biomarkers are limited and were thus explored. Methods: Patients with high grade prostate cancer and morphologic and/or immunohistochemical (IHC) NEPC features were included in this retrospective multicentre study. Clinical stage, Gleason score, and serum biomarkers were recorded. Kaplan-Meier method and log-rank test calculated and compared overall survival (OS) from time of NEPC diagnosis.Cox proportional hazards regression assessed prognostic impact of serum biomarkers at diagnosis and de novo vs TA status, adjusting for clinical stage and castration resistance. Results: 135 NEPC cases were identified. 124 (92%) were mixed tumors. 56 (41%) arose de novo. 79 (59%) were TA. 77% of those with a Gleason score (N=85/110) were grade group 5. Median PSA pre-NEPC biopsy was 11.6 ng/mL. At NEPC diagnosis, 19 (14%) had localized disease (median OS 123.0 mo); 33 (24%) non-metastatic castrate-sensitive disease (median OS 42.3 mo); 6 (4%) non-metastatic castrate-resistant disease (median OS 14.3 mo); 35 (26%) metastatic castrate-sensitive disease (median OS 17.6 mo); and 42 (31%) metastatic castrate-resistant disease (median OS 9.6 mo). Median OS for those with visceral metastases was 8.6 mo (95% CI 6.0 – 14.6), compared to patients with non-visceral metastases (11.1 mo; 95% CI 13.7 – 21.5) and no metastases (42.3 mo; 95% CI 47 – 89). Anemia (adjusted HR 1.66; 95% CI 1.05 - 2.16, p = 0.031) and NLR &gt;3 (adjusted HR 1.51; 95% CI 1.01 - 2.52, p = 0.045) were associated with increased risk of death. De novo disease, elevated LDH, serum PSA, and Gleason score were not prognostic. Conclusions: This study identifies NEPC clinical outcomes by stage, with survival poorer than expected in pure prostate adenocarcinoma. Anemia and elevated NLR &gt;3 are prognostic biomarkers that may help risk stratify and guide treatment intensification, including platinum-based chemotherapy. Further biomarker characterization of NEPC through IHC-staining pattern and genomic analysis is currently underway by this group.

Where Should Enzalutamide Be in The Metastatic Castration Resistant Prostate Cancer (mCRPC): A Multi-center Study

Objectives: Enzalutamide(ENZ) is an effective hormonal treatment modality in mCRPC. It can be used before or after docetaxel(DTX) in this setting. Herein, we aimed to show the efficacy of ENZ before or after DTX use and the factors predicting the efficacy. Methods: We retrospectively collected the data of 320 patients from 12 centers who were treated with ENZ in mCRPC. The initial stage, age, line of treatment, serum prostate-specific antigen (PSA) levels before ENZ treatment and at nadir, site of metastasis, gleason score were evaluated. Results: Median age of 320 patients were 69. At a median follow-up of 56 months, 271/320 (84.7%) disease progression and 230/320(71.9%) death had been observed. Median PFS was 11(8.9-13)) and median OS was 25(22.1-27.8) months in all patients group. Median PFS was 10(7.4-12.5) months, 11(8-13.9) months in pre-DTX and post-DTX groups respectively. Median OS was higher in the post-DTX group than the pre-DTX group (28(25.7-30.2) vs 19(15.0-22.9-46.6) (p:0.000). Gleason score?8 (HR 0.59, 95%CI 0.46-0.77, p=0.00), presence of non-visceral metastasis (HR 0.72, 95%CI 0.53-0.97, p=0.031), initial PSA value<43(median) (HR 0.70, 95%CI 0.54-0.91, p=0.009), PSA at nadir <2 (HR 0.61, 95%CI 0.44-0.85, p=0.004), >50% decline in PSA (HR 0.27, 95%CI 0.19-0.36, p=0.000) significantly predicted ENZ response regarding rPFS. Conclusion: ENZ has shown equal efficacy before and after DTX treatment in mCRPC regarding rPFS. But OS rate was significantly better in the pre-DTX group. Therefore, we recommend starting with DTX in patients who can tolerate chemotherapy in mCRPC setting. Keywords: prostate cancer, enzalutamide, docetaxel, line of treatment

Dual HER2 blockade with pertuzumab (P) and trastuzumab (T) in patients with HER2-positive metastatic breast cancer (mBC) relapsing after adjuvant treatment with T: results from a German non-interventional study (NIS) HELENA (NCT01777958)

PurposeNIS HELENA documented outcomes in clinical routine practice of first-line therapy with P plus T and docetaxel (D) of patients with advanced HER2-positive BC and prior (neo)adjuvant T.MethodsBetween 06/2013 through 07/2016, 126 patients (in-label use of P at study start = full analysis set, FAS) in 81 German study sites were included. Intense documentation period was limited to 28 treatment cycles. Maximum follow-up (FU) was 24 months (mos). Safety was assessed in the safety set (SAF = eligible patients with at least one dose of P, n = 132). Median progression-free survival (PFS) was the main parameter of interest.ResultsMean age of FAS patients was 55.1 [30.7–80.2] years, 81.7% (95.2%) were < 65 (75) years of age. 51.6% of the FAS patients were hormone receptor-positive (HR+), 91.3% had distant, 73.0% visceral, and 18.3% non-visceral metastases. Median disease-free interval was 40.2 [6.6–95.9] mos. Effectiveness (FAS): Median PFS was 18.8 [15.1; 24.2] mos. Overall response rate was 64.3% (55.6; 72.1). Median overall survival was 55.9 mos [41.2, not reached]. Safety (SAF): 93.9% of patients had an adverse event (AE), 32.6% a serious AE (SAE). AEs related to P occurred in 53.8% of SAF, SAEs related to P in 13.6%. Diarrhea was the most frequently reported related (S)AE. There were 8 (6.1%) patients with a fatal AE.ConclusionBased on the outcomes from NIS HELENA, results of dual blockade with P+T in patients relapsing after (neo)adjuvant T as reported from the CLEOPATRA study (NCT01777958) can be transferred to routine clinical practice. No new safety signals were detected.

Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial

BackgroundIntratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces...

Predicting outcomes in female germ cell patients using a modified International Germ Cell Cancer Collaborative Group classification system to guide management (100)

<b>Objectives:</b> The International Germ-Cell Cancer Collaborative Group (IGCCCG) classification guides testicular germ-cell tumor (GCT) management, but there is no validated risk-based model for female patients (pts). We devised modified IGCCCG (mIGCCCG) classifications for female GCT pts undergoing chemotherapy, validated it in a separate cohort, and investigated clinical-pathologic factors associated with survival outcomes. <b>Methods:</b> An mIGCCCG risk classification was created in a test cohort of female GCT pts treated at a single center (1990-2012). In non-dysgerminomas, good, intermediate and poor-risk groups were stratified by tumor markers or metastatic site (AFP<1,000 ng/mL, HCG <5,000 mIU/mL or LDH<1.5x upper limit of normal (ULN); AFP 1,000-10,000 ng/mL, HCG 5,000-50,000 mIU/mL or LDH 1.5-10xULN; AFP>10,000 ng/mL, HCG>50,000 mIU/mL or LDH>10xULN OR non-pulmonary visceral [excluding peritoneal] metastases, respectively). In dysgerminomas, good and intermediate-risk groups were segregated by non-visceral metastases. The mIGCCCG risk model was validated in an independent cohort treated at the same institution (1986-2020). Progression-free survival (PFS) and overall survival (OS) were estimated among all pts using the Kaplan-Meier method. Differences by clinical-demographic factors were assessed with the log-rank test and Cox proportional-hazards models. <b>Results:</b> Median age, race, stage, histology, and chemotherapy regimen were similar between the original (<i>n</i>=93) and validation (<i>n</i>=94) cohorts. As in the original cohort, both preoperative and pre-chemotherapy mIGCCCG models were significantly associated with outcome in the validation and combined cohorts (Figure 1). Using pre-chemotherapy tumor markers, estimated 3-year OS rates for good, intermediate, and poor-risk pts were 89%, 92%, and 45%, respectively, in the original cohort, whereas 100%, 80%, and 50% in the validation cohort and 94%, 88%, and 51% in the combined cohort (all p-values <0.001). Using preoperative tumor markers, estimated 3-year OS rates for good, intermediate, and poor-risk pts were 92%, 86%, and 46%, respectively, in the original cohort, whereas 100%, 86%, and 60% in the validation cohort, and 96%, 86% and 54% in the combined cohort (all p-values <0.01). On multivariable regression analyses, worse PFS outcomes were associated with the higher stage (HR: 4.3, 95% CI: 1.5-12.0, p=0.006), non-dysgerminoma histology (HR: 3.4, 95% CI: 1.8-6.4, p<0.001), and older age (HR: 1.17 per 5-year increase, 95% CI: 1.03-1.32, p=0.01). Worse OS was also associated with the higher stage (HR: 3.7, 95% CI: 1.6-8.7, p=0.003), non-dysgerminoma histology (HR: 4.8, 95% CI: 1.1-20.0, p=0.04), and older age (HR: 1.28 per 5-year increase, 95% CI: 1.09-1.50, p=0.002). <b>Conclusions:</b> A female-specific mIGCCCG risk score identifies good-risk pts with better outcomes who may benefit from less intensive chemotherapy than intermediate- and poor-risk pts requiring more intensive chemotherapy and surveillance.Fig. 1

Percutaneous cryoablation: a novel treatment option in non-visceral metastases of the abdominal cavity after prior surgery

PurposeTo assess the primary safety and oncological outcome of percutaneous cryoablation in patients with non-visceral metastases of the abdominal cavity after prior surgery.MethodsAll patients with non-visceral metastases after prior abdominal surgery, treated with percutaneous cryoablation, and at least one year of follow-up were retrospectively identified. Technical success was achieved if the ice-ball had a minimum margin of 10 mm in three dimensions on the per-procedural CT images. Complications were recorded using the Society of Interventional Radiology (SIR) classification system. Time until disease progression was monitored with follow-up CT and/or MRI. Local control was defined as absence of recurrence at the site of ablation.ResultsEleven patients underwent cryoablation for 14 non-visceral metastases (mean diameter 20 ± 9 mm). Primary tumor origin was renal cell (n = 4), colorectal (n = 3), granulosa cell (n = 2), endometrium (n = 1) and appendix (n = 1) carcinoma. Treated metastases were localized retroperitoneal (n = 8), intraperitoneal (n = 2), or in the abdominal wall (n = 4). Technical success was achieved in all procedures. After a median follow-up of 27 months (12–38 months), all patients were alive. Local control was observed in 10/14 non-visceral metastases, and the earliest local progression was detected after ten months. No major adverse events occurred. One patient suffered a minor asymptomatic adverse event.ConclusionThis proof-of-concept study suggests that cryoablation can be a minimal invasive treatment option in a selected group of patients with non-visceral metastases in the abdominal cavity after prior surgery.Graphical abstract

Hormone therapy (HT) or capecitabine (CAP) as maintenance therapy following the first-line chemotherapy in HR+/HER2-ABC/MBC: Secondary endpoint adverse effects (AEs) and toxicity report of OVERSTEP Trial (ZJCH15001/CBCSG 035).

1068 Background: OVERSTEP (NCT02597868) is a multicenter, randomized clinical trial of capecitabine (CAP) versus endocrine therapy (HT) as maintenance therapy after 1st-line CAP-based combination chemotherapy in HR+/HER2- ABC/MBC. At 2020 SABCS conference, we reported the primary endpoint (progression-free survival, PFS) at follow-up of 24.3 months, at 2021 SABCS, repoted the PFS and OS at follow-up of 41.4 months. Here, we reported the secondary endpoint Adverse effects (AEs). Methods: Total of 181 patients with HR+ and HER2- MBC were enrolled in this study from Jun, 2013 to Jan, 2019. All the patients received at least 4 cycles of CAP-based combination regimen as 1st-line salvage chemotherapy. The patients who achieved CR, PR or durable SD by RECIST criteria entered into the maintenance therapy setting (MT), and randomly (1:1 ratio) assigned to either CAP single or HT group. Randomization was done centrally with stratification by endocrine sensitive or resistance and visceral or non-visceral metastasis. After combined chemotherapy, 75.14% (n=136) cases entered into the maintenance therapy setting, and 24.86% case were disease progressed (PD) during combined chemotherapy. After a median follow-up of 41.4 months (IQR 21.57-79.23), we reported the secondary endpoint Adverse effects (AEs). Results: In PPS, hematologic toxicities in ET group and CT group were as follows, anemia (69.6% vs 64.2%), leukopenia (60.8% vs 50.8%), neutropenia (66.7% vs 31.2%), thrombocytopenia (26.1% vs 26.9%). The non-hematologic toxicities were hand-foot syndrome (HFS) (33.3 vs 41.8%), increased ALT (50.7 % vs 37.3%), increased AST (53.6% vs 37.3%), hyperbilirubinemia (32.2% vs 25.4%), fatigue (14.5% vs 10.4%), hypokalemia (5.8% vs 4.5%), pneumonia (0.0% vs 6.0%), peripheral neuropathy (4.8% vs 0.0%),etc. Duration of maintenance, the AEs in the ET group were significantly lighter, just like anemia (0.0% vs 28.4%), leukopenia (5.8% vs 17.8%), neutropenia (5.8% vs 16.4%), thrombocytopenia (2.9% vs 22.4%) et al., the non-hematologic toxicities were HFS (0.0% vs 23.9%), increased ALT (4.3% vs 16.4%), increased AST (5.8% vs 16.4%), increased bilirubin (0.0% vs 10.4%), peripheral neuropathy (5.8% vs 0.0%). Moreover, the toxicities of grade 3/4 were in the CT maintenance group, anemia was 1 case (1.5%), neutropenia 2 cases (2.99%), HFS 5 Case (7.5%) and increased AST in 1 case (1.5%). The ET maintenance group had not any grade 3/4 AEs. Conclusions: For HR+ and HER2- MBC, after 1st-line salvage combined chemotherapy, HT maintenance therapy is superior to chemotherapy (capecitabine) maintenance in terms of efficacy and safety. But, if toxicity is well managed, the safety is still tolerated during chemotherapy maintenance. Therefore, in the post-CDK4/6 period, chemotherapy is still an option. Clinical trial information: NCT02597868.

Abstract P1-17-04: Hormone therapy (HT) brings more survival benefits than capecitabine (CAP) as maintenance therapy following the 1st-line chemotherapy in HR+/HER2-ABC/MBC: Update primary endpoint of OVERSTEP(ZJCHBC001)

Abstract Background: OVERSTEP is a multicenter, randomized clinical trial of capecitabine (CAP) versus endocrine therapy (HT) as maintenance therapy after 1st-line CAP-based combination chemotherapy in HR+/HER2- ABC/MBC. At 2020 SABCS conference, we have reported the primary endpoint (progression-free survival, PFS) of the OVERSTEP (NCT02597868) trial. With a median follow-up of 24.3 months,Median PFS (mPFS) of HT cohort was significantly longer than that of CAP group (17.5 months vs. 12.2 months, HR=0.625, 95%CI: 0.429-0.909, P=0.013). In this annual meeting, we will report the update of mPFS and the secondary endpoint (overall survival, OS). Methods: HR+ and HER2- metastatic breast cancer were enrolled in this study. All patients were histologically confirmed and received at least 4 cycles of CAP-based combination regimen as 1st-line salvage chemotherapy. The patients who achieved CR, PR or durable SD by RECIST criteria entered into the maintenance therapy setting (MT), and randomly (1:1 ratio) assigned to either CAP single or HT group. Randomization was done centrally with stratification by endocrine sensitive or resistance and visceral or non-visceral metastasis. The primary endpoint was mPFS, and the secondary endpoint was overall survival (OS), safety, et al. The superiority test was performed in all patients who received at least one dose maintenance therapy. The last follow-up ended in June 30, 2021. The medium follow-up duration was 41.4 months and the OS event was mature. Results: A total of 181 eligible patients were enrolled in this study from Jun 5, 2013 to Jan 14, 2019. After combined chemotherapy, 75.14% (n=136) cases entered into the maintenance therapy setting, and 24.86% case were disease progressed (PD) during combined chemotherapy. After a median follow-up of 41.4 months (IQR 21.57-79.23), the update mPFS in HT group remained superior to CAP cohort (17.7 months vs. 12.2 months, P=0.011). In addition, the median maintenance duration of HT group was significantly longer than that of CAP group (13.8 months vs. 7.4 months, P= 0.008). For endocrine sensitive patients, mPFS was greatly prolonged in HT group compared to CAP cohort (29.3 months vs. 14.8 months, HR=0.515, 95%CI: 0.269-0.988, P=0.042). Besides, in non-visceral metastasis patients, median PFS of HT group was 25.3 months which was longer than CAP subgroup 17.0 months (HR=0.54, 95%CI: 0.300-0.972, P=0.037). However, in endocrine resistance patients, there was no significant difference between HT and CAP group (13.6 months vs. 12.0 months, HR=0.791, 95%CI: 0.499-1.253, P=0.314). There was no difference observed between HT and CAP group in visceral involved cases (14.3 months vs. 11.0 months, HR= 0.668, 95%CI: 0.410-1.089, P=0.101). The median OS was 51.7 months (95%CI: 36.614-66.786) in HT cohort and 39.8 months (95%CI:14.083-65.517) in CAP group, respectively (HR=0.882, 95%CI: 0.550-1.414, P=0.600). Conclusions: For HR+ and HER2- MBC, after 1st-line salvage combined chemotherapy, HT maintenance therapy demonstrated sustained better survival benefits than CAP, especially for hormone sensitive or non-visceral involved patients. The primary endpoint of this study was successfully reached and the median OS was prolonged by 11.9-months. Citation Format: Xiao-Jia Wang, Jian Huang, Xi-ying Shao, Li Cai, Yong-mei Yin, Li-li Zhang, Peng Shen, Yan-xia Shi. Hormone therapy (HT) brings more survival benefits than capecitabine (CAP) as maintenance therapy following the 1st-line chemotherapy in HR+/HER2-ABC/MBC: Update primary endpoint of OVERSTEP(ZJCHBC001) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-04.

HER2-low and gastric cancer: A prognostic biomarker?

e16086 Background: The role of HER2 positive (HER2+) as a prognostic biomarker for gastric/gastroesophageal junction cancer (G-GEJC) is controversial. Recently, the HER2-low (HER2l) concept has emerged and proved to predict response to trastuzumab deruxtecan in metastatic scenario. Data on HER2l prognostic value are missing. Methods: All consecutive patients with metastatic G-GEJC, tested for HER2 in the primary tumor or in the metastatic tissue before initiating first-line therapy at A.C. Camargo Cancer Center, were retrospectively recruited. The primary objective was to compare the overall survival (OS: from the metastasis diagnosis to death by any cause) between HER2l and HER2 negative (HER2-) populations. Secondarily, we aimed to compare the first-line progression-free survival (PFS) between HER2l and HER2-, to analyze prognostic factors associated with OS and to compare the OS between HER2+ and HER2l/HER2-. The HER2 immunohistochemistry (IHC) tests were performed with the Ventana anti-HER2/neu kit, by specialized gastrointestinal pathologists of the study center, using the AJCC HER2 scoring criteria for gastric cancer. In situ hybridization (ISH) was done when IHC 2+ was detected. HER2+ were IHC 3+ or 2+ amplified by ISH; HER2l, 1+ or 2+ non-amplified; HER-, 0+. Kaplan-Meier curves, Log-Rank test and Cox regression were used for survival analysis. Cox regression was used for uni and multivariate analysis. Results: From June, 2008 to July, 2020, 398 patients were included (48 HER2+; 103 HER2l; 247 HER2-). The median follow-up was 31 months (m). Median age at diagnosis was 58 years; the majority were men (62.8%), caucasian (50.8%), with gastric (81% vs 19% GEJ), diffuse (50.3%), de novo metastatic (57.0%) tumors. In comparison to HER2l/HER2-, HER2+ group had superior rates of men, GEJC, intestinal subtype and non-visceral metastasis. Central nervous system metastases were uncommon, and proportionally higher in HER2+ tumors (HER2+: 6.2%; HER2l: 2.9%; HER2-: 2.0%; p = 0.27). There were no imbalances between HER2l and HER2- groups. The median OS was similar for HER2l and HER2- (13m for both; HR 1.0, 95%CI 0.76-1.31; p = 1.0), as it was the PFS (5m for both; HR 0.84, 95%CI 0.65-1.08; p = 0.18). These results did not vary on dependence of IHC + (0 vs 1 + vs 2+). HER2+ tumors had a superior median OS (17m vs 13m for HER2l/HER2-; HR 0.70, 95%CI 0.49-0.99; p = 0.046). When ungrouping HER2l/HER2-, this numerical difference remains, with a loss of statistical significance (17m vs 13m vs 13m; HR 0.87, 95%CI 0.74-1.02; p = 0.12). HER2+, &gt; 1 line of treatment and metastasectomy were predictive for improved OS in multivariate analysis. HER2l was neither predictive for OS nor PFS. Conclusions: Although HER2-low emerged as a new predictive biomarker in metastatic gastric cancer, its prognostic value could not be proved in this study, with an absence of impact in OS. HER2+, however, was associated with improved survival.

Exploring the concepts and practices of advanced breast cancer treatment: a narrative review.

ObjectiveTo explore the concepts and practices of advanced breast cancer treatment.BackgroundMetastatic breast cancer (MBC) has become a chronic disease, with a median overall survival (OS) of around 3 years and a 5-year survival rate of about 25%. OS are strongly associated with the best available care, which consists of not only application of guidelines, but also multidisciplinary specialized care, the most efficacious medicines, and so on. Advanced breast cancer (ABC) Guidelines are the most important and authoritative guidelines for MBC.MethodsIn this review, we demonstrate the history and evolution of the global ABC Guidelines. Since 2015, Chinese multidisciplinary experts have drafted guidelines for clinical diagnosis and treatment of MBC. All of these ABC guidelines describe specialized therapeutic principles for different subtypes MBC in detail. Encouragingly, we have found that some special subtypes are hopeful of being cured, such as HER-2 positive patients with low tumor burden or HR-positive (HR+) MBC with non-visceral metastasis. In our opinion, the definition of cure of MBC is that MBC patients achieve CR and remain for more than five years after systemic treatment, including those with local therapy. Consequently, we also have conducted some researches and meaningful explorations in different subtypes of MBC. In HER2 positive MBC, our study revealed that regular HER2 circulating extracellular domain (ECD) assay can provide the real-time monitoring of tumor burden and prediction of poor outcome, and may present an important opportunity to reassess HER2 status. In HR+ MBC, we suggested that hormone therapy (HT) maintenance is the priority choice for HR+/HER2− MBC after first-line combined chemotherapy. Besides, our real-world study revealed that fulvestrant combined with ovarian suppression was an active option for premenopausal HR+/HER2- MBC. And also, we observed that everolimus (low-dose) combined with hormone therapy was still effective for HR+/HER2− MBC. For mTNBC patients, we found that THA and endostatin exhibited potential efficacy and was well tolerated in pretreated patients.ConclusionsOur concepts and practices will contribute to the design of relevant clinical research and accumulation of evidence, and cure of MBC is promising.

Abstract PS13-01: Primary analysis of OVERSTEP: A multicenter, randomized clinical trial of capecitabine or endocrine therapy as a maintenance therapy after the 1st-line chemotherapy in hormone receptor positive and HER2-negative advanced/metastatic breast cancer

Abstract Background: Endocrine therapy(ET) and Chemotherapy(CT) are used as standard maintenance therapy for HR+ and HER2- metastatic breast cancer(MBC) in clinical practice. There was no prospective study data on which is better. In OVERSTEP, we provide some strong evidence for clinical practice. Methods: OVERSTEP(NCT02597868) is a multicenter, randomized, open-label, prospective clinical trial that enrolled 181 patients in China. patients aged 18-70 years without chemotherapy for ABC/MBC previously, histologically confirmed metastatic HR+ and HER2- breast cancer, and ECOG performance status of 0-1. These patients were received capecitabine plus another chemotherapy drug as 1st-line salvage chemotherapy at least 4 cycles. The patients response are CR, PR and SD carried maintenance treatment next, randomly assigned (1:1) to receive either capecitabine single or endocrine therapy. Randomization was done centrally with stratification by endocrine resistance and visceral metastasis. The primary endpoint was progression-free survival(PFS) and analyses were base on all patients who received at least one dose maintenance therapy. We take superiority test in the 2 groups. Results: 136(75.14%) patients were randomized after combined chemotherapy to capecitabine single or endocrine therapy groups for maintenance treatment. 45(24.86%) patients are progress disease (PD) after combined chemotherapy. After a median follow-up of 24.3 months (IQR 20.46-37.25 ) in the endocrine maintenance therapy group and 24.1 months(IQR 20.67-36.77) in the Capecitabine maintenance therapy group ,the hazard ratio for PFS was 0.625(95%CI 0.429-0.909 P=0.013),Median PFS was 17.5 months(95%CI 11.544-23.856) in endocrine maintenance therapy group and 12,2 months(95%CI 11.170-13.230) in capecitabine maintenance therapy group. In endocrine sensitive group, the hazard ratio for PFS was 0.515(95%CI0.269-0.988 P=0.042), Median PFS was 29.3 months(95%CI 14.605-43.995) in endocrine maintenance therapy group and 14.8 months(95%CI 7.445-22.155) in capecitabine maintenance therapy group. In endocrine resistance group, the hazard ratio for PFS was 0.791(95%CI 0.499-1.253 P=0.314), Median PFS was 13.6 months(95%CI 9.111-18.089) in endocrine maintenance therapy group and 12.0 months(95%CI10.357-13.643) in capecitabine maintenance therapy group. In visceral metastasis group, the hazard ratio for PFS was 0.668(95%CI0.410-1.089 P=0.101), Median PFS was 14.3 months(95%CI 11.113-17.487) in endocrine maintenance therapy group and 11.0 months(95%CI 8.140-13.860) in capecitabine maintenance therapy group. In non-visceral metastasis group, the hazard ratio for PFS was 0.54(95%CI0.300-0.972 P=0.037), Median PFS was 25.3 months(95%CI 15.278-35.322) in endocrine maintenance therapy group and 17.0months(95%CI 10.783-23.217) in capecitabine maintenance therapy group. Conclusions: For HR+ and HER2- MBC, after 1st-line salvage combined chemotherapy, ET maintenance has a better survival benefits than CT,especially for ET-sensitive and non-visceral involved cases. So ET maintenance is the first choice for ABC/MBC after 1st-line combined chemotherapy. Citation Format: Jian Huang, Xiying Shao, Li Cai, Yanxia Shi, Zhanhong Chen, Ping Huang, Yongmei Yin, Lili Zhang, Peng Shen, Wenming Cao, Weiwu Ye, Yuan Huang, Caijin Lou, Lei Lei, Yabin Zheng, Weibin Zou, Junqing Chen, Xiaojia Wang. Primary analysis of OVERSTEP: A multicenter, randomized clinical trial of capecitabine or endocrine therapy as a maintenance therapy after the 1st-line chemotherapy in hormone receptor positive and HER2-negative advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-01.

Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC

BackgroundThe Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE.MethodsBetween May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months.ResultsThere were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI < 25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial.ConclusionsPOC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI < 25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses.Trial registrationThe study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

Characteristics and survival of de novo and recurrent metastatic breast cancer in New Zealand

We aim to examine the characteristics and survival of patients with de novo metastatic breast cancer (dnMBC) and recurrent metastatic breast cancer (rMBC) in New Zealand. This study included women diagnosed with dnMBC and women who developed rMBC between 2010 and 2017. The Kaplan-Meier method was used to examine cancer-specific survival. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (HR) of cancer-specific mortality by ethnicity, age, year of diagnosis, socioeconomic deprivation, site of metastases, number of metastatic sites, biomarker subtype and MBC subgroup. We included 2177 MBC patients (667 dnMBC and 1510 rMBC). The median survival of dn MBC patients was 26months compared to 18months for rMBC. There were no differences in breast-cancer specific mortality by ethnicity or socioeconomic deprivation. The adjusted HR for patients with visceral metastases compared to patients with non-visceral metastases was 1.41, and the adjusted HR for triple negative disease compared to Luminal A disease was 2.24. Compared to dnMBC, the adjusted HRs for rMBC patients with a metastatic-free interval of < 2years, 2-4years, 5-7year and 8 + years were 1.81, 1.47, 1.08 and 0.82, respectively. The survival for patients with MBC in New Zealand is very similar to other developed countries. Patients with dnMBC had a much better prognosis than those with recurrent disease. Patients with triple negative disease or non-luminal HER2 positive disease had the worst prognosis. The prognosis for patient with rMBC improved the longer the time from diagnosis to the development of metastases.

The efficacy of sequential second-line endocrine therapies (ETs) in postmenopausal estrogen receptor-positive and HER2-negative metastatic breast cancer patients with lower sensitivity to initial ETs.

Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET. This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24weeks. Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6-57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6-65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0-78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1-65.9, p = 0.018) groups. The median progression-free survival was 7.1months (95% CI: 5.6-10.6). Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.