bims-cyhorp 2022-02-13 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2022–02–13
seven papers selected by
Piotr Okupski,

CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer.
Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer.
Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone in the second-line setting-a large institutional study.
Exploratory analysis of biomarkers associated with clinical outcomes from the study of palbociclib plus endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade.
Ribociclib plus letrozole in subgroups of special clinical interest with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Subgroup analysis of the phase IIIb CompLEEment-1 trial.
Anti-HER2 therapy in metastatic breast cancer: many choices and future directions.

Future Oncol. 2022 Feb 09.

CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer.

Bulent Cetin, Chiara A Wabl, Ozge Gumusay.

  Hormone receptor (HR)-positive, HER2-negative tumors represent the most common form of metastatic breast cancer (MBC), and endocrine therapy has been the mainstay treatment for several decades. Recently, a novel drug class called CDK4/6 inhibitors in combination with endocrine therapy have remarkably improved the outcome of patients with HR-positive, HER2-negative MBC by targeting the cell cycle machinery and overcoming aspects of endocrine resistance. Several potential cell-cycle-specific and nonspecific mechanisms of resistance to CDK4/6 inhibitors have been reported in recent studies. This review discusses potential resistance mechanisms to CDK4/6 inhibitors, the use of biomarkers to guide treatment for HR-positive, HER2-negative MBC and possible approaches to overcome resistance to CDK4/6 inhibitors.

Keywords:  CDK 4/6 inhibitors; HER2-negative breast cancer; biomarkers; endocrine resistance; endocrine therapy; hormone receptor (HR) positive; resistance mechanisms

DOI:  https://doi.org/10.2217/fon-2021-0842
Ann Pharmacother. 2022 Feb 08. 10600280211073322

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer.

Farah Raheem, Henry Ofori, Lacey Simpson, Vishal Shah.

   OBJECTIVE: To review the new indication of cyclin-dependent kinase (CDK4/6) inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), axillary lymph node (LN) positive early breast cancer (EBC) at high risk of recurrence and a Ki-67 ≥20%.
DATA SOURCES: A literature search was performed through PubMed, ClinicalTrials.gov, and Food and Drug Administration (FDA) website (February 1, 2018, to December 23, 2021) to identify relevant information.
STUDY SELECTION AND DATA EXTRACTION: Human and animal studies related to pharmacology, pharmacokinetics, efficacy, and safety of abemaciclib were identified.
DATA SYNTHESIS: Addition of abemaciclib to standard of care endocrine therapy (ET) for patients with high-risk clinicopathologic features and Ki-67 ≥20% demonstrated 30% reduction in the risk of developing invasive disease and distant recurrence. At 15.5 months, abemaciclib + ET demonstrated a significant improvement in invasive disease-free survival (IDFS) vs ET alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.93, P = 0.01). At 27 months, IDFS benefit was maintained (HR, 0.70; 95% CI, 0.59-0.82, P < 0.0001). Diarrhea occurred in more than 80% of patients in the abemaciclib arm.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review describes the clinical applicability of adjuvant abemaciclib for patients with HR+, HER2- EBC at high risk for recurrence.
CONCLUSION: Adjuvant abemaciclib significantly reduces the risk for early development of invasive disease and distant recurrence in patients with HR+, HER2- node positive EBC. Longer follow-up is needed to determine the impact of adjuvant abemaciclib on late disease recurrence and survival outcomes.

Keywords:  Abemaciclib; CDK4/6 inhibitors; HER2; Ki-67 index; adjuvant therapy; breast cancer; endocrine therapy; hormone positive

DOI:  https://doi.org/10.1177/10600280211073322
Int J Cancer. 2022 Feb 08.

Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone in the second-line setting-a large institutional study.

Min Jin Ha, Akshara Singareeka Raghavendra, Nicole M Kettner, Wei Qiao, Senthil Damodaran, Rachel M Layman, K Hunt Kelly, Yu Shen, Debu Tripathy, Khandan Keyomarsi.

Cyclin-dependent-kinase-4/6 inhibitor (CDKi) plus endocrine therapy (ET) is standard of care for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer (BC). The Breast Medical Oncology database at MD Anderson Cancer Center (MDACC) was analyzed to assess effectiveness of the CDKi palbociclib plus ET compared to ET alone. From a total of 5402 advanced HR+ HER2- BC patients referred to MDACC between 1997 and 2020, we identified eligible patients who received palbociclib in combination with first- (n=778) and second-line (n=410) ET. We further identified "control" patients who received ET alone in the first- (n=2452) and second-line (n=1183) settings. Propensity score matching analysis was conducted to balance baseline demographic and clinical characteristics between palbociclib and control cohorts to assess the effect of palbociclib treatment on progression-free survival (PFS) and overall survival (OS). For propensity-matched-cohort in the first-line setting (n=708), palbociclib group had significantly longer median PFS (17.4 vs. 11.1 months; p<0.0001) compared to controls. Median OS (44.3 vs. 40.2 months) did not show a statistically significant benefit in the first line setting. However, in the second-line setting, with 380 propensity-matched-cohort, the palbociclib group had significantly longer PFS (10 vs 5 months, p<0.0001) as well as OS (33 vs 24 months; p < 0.022), compared to controls. We conclude that in this single center analysis of a large cohort of metastatic HR+ HER2- BC patients, palbociclib in combination with ET was associated with improved PFS in both first- and second-line settings and OS in the second-line setting compared with ET alone cohort.

DOI: https://doi.org/10.1002/ijc.33959
Breast. 2022 Jan 29. pii: S0960-9776(22)00014-5. [Epub ahead of print]62 52-60

Exploratory analysis of biomarkers associated with clinical outcomes from the study of palbociclib plus endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

Soohyeon Lee, Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park.

   BACKGROUND: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib + ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS.
PATIENTS AND METHODS: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models.
RESULTS: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib + ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were significantly associated to the patients with short PFS <6 month.
CONCLUSION: Of palbociclib plus ET, luminal type showed better prognosis and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy and resistance.

Keywords:  Biomarker; Next-generation sequencing; Palbociclib; Progression-free survival

DOI:  https://doi.org/10.1016/j.breast.2022.01.014
Cancer Res. 2022 Feb 11. pii: canres.3062.2021. [Epub ahead of print]

CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade.

Jingshan Tong, Xiao Tan, Xiangping Song, Man Gao, Denise Risnik, Suisui Hao, Kaylee Ermine, Peng Wang, Hua Li, Yi Huang, Jian Yu, Lin Zhang.

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death (ICD) of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TNF-related apoptosis-inducing ligand (TRAIL), 5-fluorouracil (5-FU) chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3062
Breast. 2022 Jan 31. pii: S0960-9776(22)00023-6. [Epub ahead of print]62 75-83

Ribociclib plus letrozole in subgroups of special clinical interest with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Subgroup analysis of the phase IIIb CompLEEment-1 trial.

Paul Cottu, Alistair Ring, Hikmat Abdel-Razeq, Paolo Marchetti, Fatima Cardoso, Javier Salvador Bofill, Miguel Martín, Lakshmi Menon-Singh, Jiwen Wu, Michelino De Laurentiis.

   BACKGROUND: The phase IIIb CompLEEment-1 study evaluated ribociclib plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Outcomes were investigated in the following subgroups: central nervous system (CNS) metastases, prior chemotherapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and visceral metastases plus prior chemotherapy for advanced disease or ECOG PS 2.
PATIENTS AND METHODS: Patients with HR+, HER2- ABC without prior hormonal treatment for advanced disease received oral ribociclib (600 mg once daily, 3 weeks on/1 week off) plus letrozole (2.5 mg once daily, continuous). Primary endpoint was safety/tolerability, assessed via occurrence of adverse events (AEs); key secondary endpoints included time to progression (TTP), overall response rate, and clinical benefit rate.
RESULTS: 51 patients had CNS metastases, 194 received prior chemotherapy for advanced disease, 112 had ECOG PS 2, 146 had visceral metastases plus prior chemotherapy, and 77 had visceral metastases plus ECOG PS 2. Safety results were consistent with those in the overall CompLEEment-1 population; no new safety concerns were identified. The AE profile was manageable with low rates of discontinuations due to AEs. TTP in patients with CNS metastases was consistent with the overall study population and shorter for other patient subgroups. Each patient subgroup achieved meaningful clinical benefit from treatment, consistent with the overall population.
CONCLUSION: These findings confirm the clinical benefit of ribociclib plus endocrine therapy in high-risk patient subgroups of clinical interest commonly underrepresented in clinical trials.

Keywords:  Advanced breast cancer; CDK4/6 inhibitor; Endocrine therapy; Ribociclib

DOI:  https://doi.org/10.1016/j.breast.2022.01.016
Cancer Metastasis Rev. 2022 Feb 10.

Anti-HER2 therapy in metastatic breast cancer: many choices and future directions.

Carrie S Wynn, Shou-Ching Tang.

  Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action.

Keywords:  Anti-HER2 therapy; Drug resistance; HER2 + metastatic breast cancer; New drugs; Treatment

DOI:  https://doi.org/10.1007/s10555-022-10021-x