bims-cyhorp 2021-09-05 papers

Issue of 2021‒09‒05
five papers selected by
Piotr Okupski

Autops Case Rep. 2021 ;11 e2021309

Palbociclib in breast cancer neoadjuvant setting.

Sílvia Alexandra Cabral Duarte, Daniela Silva Pádua de Azevedo, Teresa Tomé Ribeiro Malheiro Sarmento, Marta Verónica Velho Sousa.

Cyclin-dependent kinase 4/6 inhibitors represent a major advance in breast cancer treatment, emerging as the standard of care of the initial treatment of hormone receptor-positive and HER2-negative metastatic breast cancer. Their activity in this subset of patients leads to interest in their use in the adjuvant and neoadjuvant settings. This case report presents a real-life case of cyclin-dependent kinase 4/6 inhibitors use in a patient initially considered to have stage IV luminal HER2-negative breast cancer with liver metastasis. The discrepancy of treatment response between the breast tumor and liver node led to a repetition of the liver biopsy, which revealed metastasis of a neuroendocrine tumor of unknown primary. The breast tumor showed a partial response, and the initial therapeutic strategy was then redefined for curative intent. While cyclin-dependent kinase 4/6 inhibitors are not yet approved for clinical practice in the neo / adjuvant treatment of hormone receptor-positive breast cancer, this case report portrays a successful example of its application in a neoadjuvant setting.

Keywords: Breast Neoplasms; Case Reports; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6

DOI: https://doi.org/10.4322/acr.2021.309

Int J Cancer. 2021 Aug 30.

The implementation of CDK 4/6 inhibitors and its impact on treatment choices in HR+/HER2- advanced breast cancer patients: A study of the Dutch SONABRE Registry.

Marissa Meegdes, Sandra M E Geurts, Frans L G Erdkamp, M Wouter Dercksen, Birgit E P J Vriens, Kirsten N A Aaldering, Manon J A E Pepels, Linda M H van de Winkel, Nathalie J A Teeuwen, Maaike de Boer, Vivianne C G Tjan-Heijnen.

In August 2017, CDK4/6 inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2- ABC in 2009-2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The two-year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing-risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1st 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009-2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n=214), 50% (95%CI:43-57) received CDK4/6 inhibitors within two years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n=417), 31% (95%CI:27-36) received CDK4/6 inhibitors within two years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first-line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first-line: 29% to 13%; second-line: 26% to 19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within two years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first-line therapy.

Keywords: CDK4/6 inhibitors; breast cancer; implementation; metastatic disease; real-world

DOI: https://doi.org/10.1002/ijc.33785

Clin Transl Med. 2021 Aug;11(8): e503

Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2-Hippo signaling pathway.

Yi Zhang, Long-Jun He, Lin-Lin Huang, Sheng Yao, Nan Lin, Ping Li, Hui-Wen Xu, Xi-Wen Wu, Jian-Liang Xu, Yi Lu, Yan-Jie Li, Sen-Lin Zhu.

Intrinsic resistance to CDK4/6 inhibitors hinders their clinical utility in cancer treatment. Furthermore, the predictive markers of CDK4/6 inhibitors in gastric cancer (GC) remain incompletely described. Here, we found that PAX6 expression was negatively correlated with the response to palbociclib in vitro and in vivo in GC. We observed that the PAX6 expression level was negatively correlated with the overall survival of GC patients and further showed that PAX6 can promote GC cell proliferation and the cell cycle. The cell cycle is regulated by the interaction of cyclins with their partner serine/threonine cyclin-dependent kinases (CDKs), and the G1/S-phase transition is the main target of CDK4/6 inhibitors. Therefore, we tested whether PAX6 expression was correlated with the GC response to palbociclib. We found that PAX6 hypermethylates the promoter of LATS2 and inactivates the Hippo pathway, which upregulates cyclin D1 (CCND1) expression. This results in a suppressed response to palbociclib in GC. Furthermore, we found that the induction of the Hippo signaling pathway or treatment with a DNA methylation inhibitor could overcome PAX6-induced palbociclib resistance in GC. These findings uncover a tumor promoter function of PAX6 in GC and establish overexpressed PAX6 as a mechanism of resistance to palbociclib.

Keywords: CDK4/6 inhibitor; DNA methylation; Hippo signaling pathway; PAX6

DOI: https://doi.org/10.1002/ctm2.503

NPJ Breast Cancer. 2021 Aug 31. 7(1): 111

Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition.

Diar Aziz, Neil Portman, Kristine J Fernandez, Christine Lee, Sarah Alexandrou, Alba Llop-Guevara, Zoe Phan, Aliza Yong, Ashleigh Wilkinson, C Marcelo Sergio, Danielle Ferraro, Dariush Etemadmoghadam, David D Bowtell, , Violeta Serra, Paul Waring, Elgene Lim, C Elizabeth Caldon.

Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.

DOI: https://doi.org/10.1038/s41523-021-00312-x