Excellent Response to Atezolizumab After Clinically Defined Hyperprogression Upon Previous Treatment With Pembrolizumab in Metastatic Triple-Negative Breast Cancer: A Case Report and Review of the Literature

Immunotherapy with immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors, has revolutionized the systematic treatment of advanced and metastatic solid tumors. However, the response rate to ICIs is unsatisfactory, and unexpected hyperprogressive disease (HPD) is even observed in a small subgroup of patients. Patients with HPD usually have worsening clinical symptoms and poorer survival, and therapeutic strategies are extremely limited. Here, we presented a patient with HPD who had used a PD-L1 inhibitor and was highly responsive to the sequential use of a PD-1 inhibitor. A 67-year-old woman with metastatic triple-negative breast cancer was treated with pembrolizumab plus chemotherapy after progression on previous multiple-line chemotherapy treatments. After 2 cycles of treatments, she rapidly developed HPD, as confirmed by radiological evaluation and worsening symptoms. At that time, pembrolizumab was discontinued, and she switched to the PD-L1 inhibitor atezolizumab plus chemotherapy. This patient partially responded to atezolizumab plus chemotherapy without experiencing severe drug-related adverse effects. This is the first reported case of metastatic breast cancer in a patient with radiologically confirmed HPD after pembrolizumab therapy in which successful rechallenge with atezolizumab relieved clinical symptoms. Further studies with larger sample sizes involving a deeper translational investigation of HPD are needed to confirm the efficacy and mechanism of sequential application of different ICIs for the clinical management of HPD.

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Radiotherapy with the anti-programmed cell death ligand-1 immune checkpoint blocker avelumab: acute toxicities in triple-negative breast cancer

Medical Oncology ◽

10.1007/s12032-018-1228-y ◽

2018 ◽

Vol 36 (1) ◽

Cited By ~ 4

Author(s):

Eliana La Rocca ◽

Michela Dispinzieri ◽

Laura Lozza ◽

Gabriella Mariani ◽

Serena Di Cosimo ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Triple Negative

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Efficacy and safety profiles of programmed cell death-1/programmed cell death ligand-1 inhibitors in the treatment of triple-negative breast cancer: A comprehensive systematic review

Oncology Reviews ◽

10.4081/oncol.2019.425 ◽

2019 ◽

Vol 13 (2) ◽

Author(s):

Gilbert Lazarus ◽

Jessica Audrey ◽

Anthony William Brian Iskandar

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Cell Death ◽

Programmed Cell Death ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Effects ◽

Efficacy And Safety ◽

Programmed Cell Death 1 ◽

Grade 3

Triple-negative breast cancer (TNBC) is associated with worse prognosis, with limited treatment regiments available and higher mortality rate. Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) showed great potentials in treating malignancies and may serve as potential therapies for TNBC. This systematic review aims to evaluate the efficacy and safety profiles of PD-1/PD-L1 inhibitors in the treatment of TNBC. Literature search was performed via PubMed, EBSCOhost, Scopus, and CENTRAL databases, selecting studies which evaluated the use of anti-PD-1/PDL1 for TNBC from inception until February 2019. Risk of bias was assessed by the Newcastle-Ottawa Scale (NOS). Overall, 7 studies evaluating outcomes of 1395 patients with TNBC were included in this systematic review. Anti-PD-1/PD-L1 showed significant antitumor effect, proven by their promising response (objective response rate (ORR), 18.5-39.4%) and survival rates (median overall survival (OS), 9.2-21.3 months). Moreover, anti- PD-1/PD-L1 yielded better outcomes when given as first-line therapy, and overexpression of PD-L1 in tumors showed better therapeutic effects. On the other hands, safety profiles were similar across agents and generally acceptable, with grade ≥3 treatment- related adverse effects (AEs) ranging from 9.5% to 15.6% and no new AEs were experienced by TNBC patients. Most grade ≥3 AEs are immune-mediated, which are manifested as neutropenia, fatigue, peripheral neuropathy, and anemia. PD-1/PD-L1 inhibitors showed promising efficacy and tolerable AEs, and thus may benefit TNBC patients. Further studies of randomized controlled trials with larger populations are needed to better confirm the potential of these agents.

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Targeted Therapies in Triple-Negative Breast Cancer

Breast Care ◽

10.1159/000433622 ◽

2015 ◽

Vol 10 (3) ◽

pp. 159-166 ◽

Cited By ~ 33

Author(s):

Frederik Marmé ◽

Andreas Schneeweiss

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Chemotherapy Resistance ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Receptor Subtype

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed.

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Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

Frontiers in Oncology ◽

10.3389/fonc.2021.570623 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xin-yu Ren ◽

Yu Song ◽

Jing Wang ◽

Long-yun Chen ◽

Jun-yi Pang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Low Frequency ◽

Clinicopathological Parameters ◽

Tissue Samples

PurposeTo investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters.MethodsWe retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed.ResultsThe median age of the cohort was 49 years (range: 24–90 years) with a median follow-up period of 68 months (range: 1–170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible EPCAM deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival.ConclusionsThe incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.

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Integration of tumour infiltrating lymphocytes, programmed cell-death ligand-1, CD8 and FOXP3 in prognostic models for triple-negative breast cancer: Analysis of 244 stage I–III patients treated with standard therapy

European Journal of Cancer ◽

10.1016/j.ejca.2020.05.014 ◽

2020 ◽

Vol 136 ◽

pp. 7-15 ◽

Cited By ~ 2

Author(s):

Maria Vittoria Dieci ◽

Vassilena Tsvetkova ◽

Gaia Griguolo ◽

Federica Miglietta ◽

Giulia Tasca ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Triple Negative Breast Cancer ◽

Standard Therapy ◽

Triple Negative ◽

Stage I ◽

Prognostic Models ◽

Tumour Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

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Atezolizumab and Pembrolizumab in Triple-Negative Breast Cancer: A Meta-Analysis

10.20944/preprints202105.0546.v1 ◽

2021 ◽

Author(s):

Mahwish Amin ◽

Shaiza Sharif ◽

Waleed Asghar ◽

Humaira Sadaf ◽

Azza Sarfraz ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Triple Negative Breast Cancer ◽

Effect Size ◽

Triple Negative ◽

Meta Analysis ◽

Control Groups ◽

Cohen’S D ◽

Positive Effect

Triple negative breast cancer (TNBC) has a higher mRNA expression of programmed cell death ligand 1 (PD-L1) which is a ligand to programmed cell death protein 1 (PD-1). The binding of the ligand leads to suppressed activity of T-cell-mediated immune response against cancer cells. The approval of anti-PD-L1 drugs including pembrolizumab and atezolizumab in subgroups of TNBC offer potential improvement to the current treatment regimens available for TNBC. We conducted a meta-analysis to review the efficacy of pembrolizumab and atezolizumab for the treatment of TNBC in both adjuvant and neo-adjuvant settings. A systematic strategy was used as per the PRISMA 2020 statement. All statistical analyses were conducted using Review Manager 5.4. Outcome measures included objective response rate, progression free survival, overall survival in adjuvant therapy groups, and pathological complete response rates in neoadjuvant groups. Six clinical trials were included. For adjuvant therapies, the ORR (OR=1.26, P = 0.04) of Atezolizumab/Pembrolizumab plus chemotherapy was higher in intention to treat (ITT) arms than the placebo groups in TNBC. A positive effect size was found for PFS in the ITT arms (Cohen’s d = 1.55, P<0.001). The Atezolizumab plus chemotherapy group had a positive effect size for OS compared to the control groups (Cohen’s d = 0.52, P<0.001). In the neo-adjuvant setting, patients in ITT arms had higher pCR rates as compared to the control groups (OR= 1.61, P = 0.001). Our findings collate evidence of pembrolizumab and atezolizumab as a viable treatment option among patients with TNBC with PDL1+ subgroups deriving benefits.

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The Association of Tumor-Infiltrating Lymphocytes and Programmed Cell Death 1 Expression with the Incidence of Distant Metastasis in Triple-Negative Breast Cancer Subjects in Sanglah General Hospital, Bali, Indonesia

Case Reports in Oncology ◽

10.1159/000514272 ◽

2021 ◽

pp. 347-351

Author(s):

I Wayan Sudarsa ◽

I Putu Ari Gunawan ◽

Ida Bagus Tjakra Wibawa Manuaba

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

General Hospital ◽

Triple Negative Breast Cancer ◽

Distant Metastasis ◽

Triple Negative ◽

Tumor Infiltrating Lymphocytes ◽

Programmed Cell Death 1 ◽

Infiltrating Lymphocytes

The triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a high rate of distant metastasis. The tumor immunity microenvironment plays an important role, including tumor-infiltrating lymphocytes (TIL) and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1), in promoting TNBC aggressiveness. This study aimed to determine the association of TIL and PD-L1 expression with the incidence of distant metastasis in TNBC. This study is a cross-sectional study involving TNBC subjects at Sanglah General Hospital, Denpasar, conducted in 2019. The parameters analyzed were the expression of TIL, PD-L1, and the incidence of distant metastasis. The expression of TIL was analyzed histopathologically while PD-L1 was measured with Ventana PD-L1 kit test. Subject characteristics were obtained from medical records. Data were collected and analyzed by SPSS 22.0. As many as 31 subjects with TNBC were included in this study, with 51.6% subjects with distant metastasis. The majority of subjects with distant metastasis had low TIL and low tumoral PD-L1 but high PD-L1 stromal in TIL. From statistical analysis, only PD-L1 stromal in TIL expression was associated significantly with distant metastasis (p = 0.043). In conclusion, there was a significant association between PD-L1 stromal in TIL and the incidence of distant metastasis in TNBC.

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