PD-L1 expression + HER-2 overexpression

The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care...The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy.

PD-L1 is positive in most of the ISMC cases, while HER2 is amplified or lowly expressed in a small portion of them. Thus, it is possible to treat ISMC patients with therapies targeting PD-L1 and therapy targeting HER2.

Our data suggest that HER2 is more frequently expressed in conventional UC than in divergent subtypes. Additionally, PD-L1 has a higher expression level in lower urinary tract UC compared to upper. However, PD-L1 and HER2 expression are not related to gender or tumor stage in UC.

We conclude that certain parameters of poor prognosis such as high histologic grade of the tumour, presence of lymphovascular invasion, clinically positive axillary lymph nodes and high IC count correlate with PD-L1 expression in HER2-positive BC, but we did not find the potential of PD-L1 to predict response to anti-HER2 neoadjuvant treatment.

Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration.

P1/2, N=240, Recruiting, AstraZeneca | Trial completion date: Aug 2024 --> Nov 2024 | Trial primary completion date: Aug 2024 --> Nov 2024

While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.

Second-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC.

T-DXd demonstrated clinically meaningful ORR in patients with HER2-expressing gynecological tumors, irrespective of number of prior lines of therapy, use of prior HER2 or TOP1 inhibitor therapy, and presence or absence of biomarkers relevant to individual cohorts. Safety of T-DXd was consistent with the known profile. These data support T-DXd as a potential treatment for patients with gynecological HER2-expressing tumors who have progressed on prior therapy.

The HER2+ status may be related to genetic characteristics that appear more frequently in older age, which suggests a potential for predicting the recurrence and response to BCG treatment. Additionally, analyzing TME trends of aggressive adaptive immune response characterized by HER2 expression provides insight into recurrence and BCG response mechanisms.

Almost all TNBC cases can be classified according to treatable targets.

She had been taking adjuvant letrozole at the time of presentation. This case also highlights the benefits of using advanced and highly sensitive CSF assays to diagnose and surveil leptomeningeal disease and to assess HER2 signaling. This case is well-timed especially in the era of next-generation, CNS penetrating, potent HER2-directed antibody-drug conjugate like T-DXd which can mount antitumor activity even with minimal HER2 expression in tumors.

In contrast, the benefit of the anti-Trop-2 antibody-drug conjugate (ADC) Sacituzumab govitecan (SG) does not appear confined to patients with tumours expressing high levels of Trop-2, leading to its potential utility for any patient with an estrogen receptor (ER)-negative, HER2-negative advanced breast cancer (ABC). Most recently, low levels of HER2 expression, detected in up to 60% of TNBC, predicts benefit from the potent HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd), defining an additional treatment option for this sub-group. Regrettably, despite recent advances, the median survival of TNBC continues to lag far behind the approximately 5 years now expected for patients with ER-positive or HER2-positive breast cancers. We review the data supporting immunotherapy, ADCs, and targeted agents in subgroups of patients with TNBC, and current clinical trials that may pave the way to further advances in this challenging disease.

Our data demonstrated a link between IHC/ISH characteristics of GC and clinical outcomes. IHC/ISH based molecular classification may be helpful in predicting the survival.

P1/2, N=203, Recruiting, AstraZeneca | Active, not recruiting --> Recruiting

During this timeframe, 73 patients received pembrolizumab monotherapy, among whom a small portion showed a durable response. Comprehensive genomic and IHC profiling may help identify potential candidates for targeted immunotherapy in patients with cervical cancer.

P=N/A, N=80, Recruiting, Ain Shams University | Not yet recruiting --> Recruiting

P1/2, N=240, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2023 --> Aug 2024 | Trial primary completion date: Jun 2023 --> Aug 2024

This work shows how the expansion of the HER2 spectrum might raise problems in reproducibility, especially in biopsy specimens, decreasing interlaboratory and interobserver concordance. If controlled trials confirm the promising activity of novel anti-HER2 agents in HER2-low gastro-oesophageal cancers, a shift in the interpretation of HER2 status may need to be pursued.

CTC can be used as a real-time surrogate for molecular profiling of PD-L1, HER2 and EGFR expression. These CTC cell surface markers offer alternative for immunotherapy or targeted therapies decisions in a adenocarcinomas.

P1/2, N=210, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2024 --> Jun 2023

In the case of HER-2 intratumoral heterogeneity, it is necessary to pay attention to both HER-2 positive and negative regions, and evaluate subtype separately as far as possible. For HER-2 intratumoral heterogeneous breast cancer containing triple negative components, the treatment mode can be optimized by refining the intratumoral expression of PD-L1.

PD-L1 expression was significantly positively correlated with HER2 expression in OSCC. The results provide valuable insight for the future application of HER2-targeted therapy combined with immunotherapy in OSCC.

High concordance between HER2 IHC and ERBB2 expression/amplification was observed. Differences in the genomic landscape and ADC target expression of ERBB2-high vs -low UC may provide rationale for combination treatment strategies with HER2-blocking antibodies. The association between high ERBB2 expression and survival advantage warrants further investigation.

In the DESTINY-Gastric01 trial, a novel HER2-targeted antibody-drug conjugate Trastuzumab deruxtecan proved to be effective in HER2-low disease also, paving the way for novel therapeutic scenarios... This study shows how the expansion of the HER2 spectrum might raise problems in reproducibility, especially in biopsy specimens, decreasing interlaboratory and interobserver concordance. If controlled trials confirm the promising activity of novel anti-HER2 agents in HER2-low gastroesophageal cancers, a shift in the interpretation of HER2 status may need to be pursued.

Dysregulation of clock genes is strongly associated with breast cancer subtype and survival. Higher CS is associated with TNBC and PDL1 expression and supports the use of checkpoint inhibitors. Prognosis is better with low expression of TIMELESS and CLOCK and high expression of CRY2 and PER2/3, suggesting a role in tumor development and maintenance.

PD-L1 expression was demonstrated in 3 out of 13 HER-3‑positive patients and 2 out of 2 HER-3‑positive TNBC patients. There was a strong correlation between positive HER-3 and PD-L1 TNBC expression (p = Keywords: breast cancer, HER family, overexpression, HER-3, HER-2, PD-L1, TNBC.

Peripheral PD-1/PD-L1 expression had a significant consistency with PD-L1 expression in tumor microenvironment and could act as an alternative choice of tissue detection, for the patients intolerable of biopsy.

Improvements in micro-array-based gene expression profiling can help us to better delineate the tumor behavior and help us with treatment. Figure: Figure 1: a. CT abdomen - partially calcified gastric mass; b. EGD - A large infiltrative and ulcerated, noncircumferential mass on the lesser curvature of the gastric body; c. & d. Histopathology - H&E stain (20 x): gastric mucosa infiltrated by carcinoma cells with a signet-ring morphology.

he PD-L1 expression prevalence in a cohort of the Colombian population has been studied for the first time. The prevalence of PD-L1 CPS score ≥10 was less for UC and EC samples compared with previous reports for these tumors in other clinical trials as well as for HNSCC with a CPS score of ≥20. Further studies are needed, focused on evaluating PD-L1 expression in Colombian patients influenced by their own environment and genetics, to define characteristics that support decision-making for tumor treatment.

P=N/A, N=80, Not yet recruiting, Ain Shams University | Trial completion date: Apr 2023 --> Aug 2023 | Initiation date: Mar 2022 --> Aug 2022 | Trial primary completion date: Mar 2023 --> Aug 2023

Approximately 52.9% (9/17) of HER2-positive patients treated with Trastuzumab targeted therapy, overall survival was higher in HER2-positive patients than in HER2-negative patients (P=0.211)...There was no significant difference in overall survival between TILs and Ki67 co-expression (P=0.452). Pure AC HER2-positive patients have higher levels of TILs and Ki67, HER2 negative and TILs ≥50% patients may have higher PD-L1 expression, which may be helpful for screening patients with different immune statuses to guide effective clinical treatment combinations.

The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody-drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer-based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

Recently, KEYNOTE-522 study showed that anti-PD-L1 antibody (pembrolizumab) cooperated with neoadjuvant chemotherapy increased pCR rate in TNBC patients. Major inclusion and exclusion criteria are followings; 1) histologically confirmed TNBC, 2) received anthracycline and taxane based NAC followed by complete breast surgery, 3) residual disease after NAC must be ≥ 1 cm in the greatest dimension, and/or have macroscopically positive lymph nodes. The study is open with 13 patients enrolled at the time of submission.

Discordance may be attributed to tissue heterogeneity. Substantial overlap between PD-L1 positivity and HER2 positivity supports combined administration of HER2-targeted agents and checkpoint inhibitors.

PDL-1 is a promising prognostic and therapeutic target in GC that may direct the selection of patients for immunotherapy and checkpoint-blockade (pembrolizumab) therapy.

RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with mUC and a manageable safety profile. A randomized study of RC48-ADC and toripalimab vs. platinum-based chemotherapy in previously untreated la/mUC patients is ongoing.

The novel fluorescent amplification system allows for tuning of signal to visualize both low and high expressors within the same tissue sample. This multiplexed approach is quantitative and tunable, enabling a highly sensitive and specific evaluation of immune infiltrate across tissues with a wide range of Her2 expression levels.

PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression.

Treatment with Nivolumab exhibited similar effects...(4) Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.

P=N/A, N=80, Not yet recruiting, Ain Shams University

Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.