CDK4/6 inhibitors: The Devil is in the Detail.

PURPOSE OF REVIEW: Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. RECENT FINDINGS: Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

Persistence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor-positive (HR +) breast cancer.

PURPOSE: Extending adjuvant endocrine therapy (ET) beyond the standard 5 years offers added protection against late breast cancer recurrences in women with early-stage hormone receptor-positive (HR +) breast cancer. Little is known about treatment persistence to extended ET (EET) and the role that genomic assays may play. In this study, we evaluated persistence to EET in women who had Breast Cancer Index (BCI) testing. METHODS: Women with stage I-III HR + breast cancer who had BCI testing after at least 3.5 years of adjuvant ET and ≥ 7 years of follow-up after diagnosis were included (n = 240). Data on medication persistence was based on prescriptions in the electronic health record. RESULTS: BCI predicted 146 (61%) patients to have low - BCI (H/I)-low - and 94 (39%) patients to have high likelihood of benefit from EET (BCI (H/I)-high). Continuation of ET after BCI occurred in 76 (81%) (H/I)-high and 39 (27%) (H/I)-low patients. Non-persistence rates were 19% in the (H/I)-high and 38% in the (H/I)-low group. The most common reason for non-persistence was intolerable side effects. Patients on EET underwent more DXA bone density scans than those who stopped ET at 5 years (mean 2.09 versus 1.27; p < 0.001). At a median follow-up of 10 years from diagnosis, there were 6 metastatic recurrences. CONCLUSIONS: In patients who continued ET after BCI testing, the rates of persistence to EET were high, particularly in patients with predicted high likelihood of benefit from EET. Use of EET is associated with increased use of DXA scans.

Pharmacology and pharmacokinetics of elacestrant.

Elacestrant, a novel oral selective estrogen receptor (ER) degrader (SERD), was approved by the Food and Drug Administration (FDA) on January 27, 2023, for use in patients with ER and/or progesterone receptor (PR)-positive and HER2-negative metastatic breast cancer whose tumors harbor an ESR1 missense mutation (ESR1-mut), after at least one line of endocrine therapy (ET). The FDA made its decision based on the randomized phase 3 EMERALD trial, which met its primary endpoint of improved median progression-free survival (mPFS) with elacestrant monotherapy versus standard-of-care endocrine monotherapy in the overall intention to treat population; however, this benefit was largely driven by the ESR1-mut cohort. Elacestrant is a dose-dependent mixed ER agonist/antagonist, which at high doses acts as a direct ER antagonist as well as selective downregulator of ER. It is 11% bioavailable, primarily metabolized by CYP3A4 in the liver and excreted in feces. This leads to drug-drug interactions with strong CYP3A4 inhibitors and inducers, such as itraconazole and rifampin, respectively. In accordance with its clearance route, dose reduction is recommended in patients with moderate hepatic dysfunction but not in renal dysfunction. Studies evaluating elacestrant in severe hepatic dysfunction as well as in patients from racial and ethnic minority groups are ongoing. Overall, elacestrant is the first orally bioavailable SERD approved by the FDA for use in patients with metastatic breast cancer. Current clinical trials are ongoing evaluating it in the adjuvant setting in patients with early stage ER-positive breast cancers.

Oncotype DX results increase concordance in adjuvant chemotherapy recommendations for early-stage breast cancer.

Adjuvant chemotherapy recommendations for ER+/HER2- early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2- eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2- eBC.

Case report: abemaciclib-induced syndrome of inappropriate antidiuretic hormone (SIADH) without underlying kidney injury in a patient with early-stage estrogen receptor (ER)+ breast cancer.

The CDK4/6 inhibitor, abemaciclib, is now the standard of care adjuvant therapy for patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) tumors at high risk of recurrence. Real-world usage uncovers emerging side effects that may have been previously unreported in clinical trials. Here, we present the clinical course of a patient who developed a syndrome of inappropriate antidiuretic hormone (SIADH) without underlying kidney injury due to abemaciclib use.

Molecular differences between younger versus older ER-positive and HER2-negative breast cancers.

The RxPONDER and TAILORx trials demonstrated benefit from adjuvant chemotherapy in patients age ≤ 50 with node-positive breast cancer and Recurrence Score (RS) 0-26, and in node-negative disease with RS 16-25, respectively, but no benefit in older women with the same clinical features. We analyzed transcriptomic and genomic data of ER+/HER2- breast cancers with in silico RS < 26 from TCGA (n = 530), two microarray cohorts (A: n = 865; B: n = 609), the METABRIC (n = 867), and the SCAN-B (n = 1636) datasets. There was no difference in proliferation-related gene expression between age groups. Older patients had higher mutation burden and more frequent ESR1 copy number gain, but lower frequency of GATA3 mutations. Younger patients had higher rate of ESR1 copy number loss. In all datasets, younger patients had significantly lower mRNA expression of ESR1 and ER-associated genes, and higher expression of immune-related genes. The ER- and immune-related gene signatures showed negative correlation and defined three subpopulations in younger women: immune-high/ER-low, immune-intermediate/ER-intermediate, and immune-low/ER-intermediate. We hypothesize that in immune-high cancers, the cytotoxic effect of chemotherapy may drive the benefit, whereas in immune-low/ER-intermediate cancers chemotherapy induced ovarian suppression may play important role.

Clinical Outcomes and Immune Markers by Race in a Phase I/II Clinical Trial of Durvalumab Concomitant with Neoadjuvant Chemotherapy in Early-Stage TNBC.

PURPOSE: The incidence of triple-negative breast cancer (TNBC) is higher among Black or African American (AA) women, yet they are underrepresented in clinical trials. To evaluate safety and efficacy of durvalumab concurrent with neoadjuvant chemotherapy for stage I-III TNBC by race, we enrolled additional AA patients to a Phase I/II clinical trial. PATIENTS AND METHODS: Our study population included 67 patients. The primary efficacy endpoint was pathologic complete response (pCR; ypT0/is, N0) rate. χ2 tests were used to evaluate associations between race and baseline characteristics. Cox proportional hazards models were used to assess association between race and overall survival (OS) and event-free survival (EFS). Multivariate logistic regression analyses were used to evaluate associations between race and pCR, immune-related adverse events (irAE) and recurrence. RESULTS: Twenty-one patients (31%) self-identified as AA. No significant associations between race and baseline tumor stage (P = 0.40), PD-L1 status (0.92), and stromal tumor-infiltrating lymphocyte (sTIL) count (P = 0.57) were observed. pCR rates were similar between AA (43%) and non-AA patients (48%; P = 0.71). Three-year EFS rates were 78.3% and 71.4% in non-AA and AA patients, respectively [HR, 1.451; 95% confidence interval (CI), 0.524-4.017; P = 0.474]; 3-year OS was 87% and 81%, respectively (HR, 1.72; 95% CI, 0.481-6.136; P = 0.405). The incidence of irAEs was similar between AA and non-AA patients and no significant associations were found between irAEs and pathologic response. CONCLUSIONS: pCR rates, 3-year OS and EFS after neoadjuvant immunotherapy and chemotherapy were similar in AA and non-AA patients. Toxicities, including the frequency of irAEs, were also similar.

A precision medicine approach to metabolic therapy for breast cancer in mice.

Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.

Cancer Relevance of Human Genes.

BACKGROUND: We hypothesize that genes that directly or indirectly interact with core cancer genes (CCGs) in a comprehensive gene-gene interaction network may have functional importance in cancer. METHODS: We categorized 12 767 human genes into CCGs (n = 468), 1 (n = 5467), 2 (n = 5573), 3 (n = 915), and more than 3 steps (n = 416) removed from the nearest CCG in the Search Tool for the Retrieval of Interacting Genes/Proteins network. We estimated cancer-relevant functional importance in these neighborhood categories using 1) gene dependency score, which reflects the effect of a gene on cell viability after knockdown; 2) somatic mutation frequency in The Cancer Genome Atlas; 3) effect size that estimates to what extent a mutation in a gene enhances cell survival; and 4) negative selection pressure of germline protein-truncating variants in healthy populations. RESULTS: Cancer biology-related functional importance of genes decreases as their distance from the CCGs increases. Genes closer to cancer genes show greater connectedness in the network, have greater importance in maintaining cancer cell viability, are under greater negative germline selection pressure, and have higher somatic mutation frequency in cancer. Based on these 4 metrics, we provide cancer relevance annotation to known human genes. CONCLUSIONS: A large number of human genes are connected to CCGs and could influence cancer biology to various extent when dysregulated; any given mutation may be functionally important in one but not in another individual depending on genomic context.

Predictive Markers of Response to Neoadjuvant Durvalumab with Nab-Paclitaxel and Dose-Dense Doxorubicin/Cyclophosphamide in Basal-Like Triple-Negative Breast Cancer.

PURPOSE: We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC). EXPERIMENTAL DESIGN: Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial. RESULTS: Gene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK-STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial-mesenchymal transition, extracellular matrix, and TGFß pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/ß-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR. CONCLUSIONS: The TGFß pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.

Comprehensive Analysis of Metabolic Isozyme Targets in Cancer.

Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here, we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using The Cancer Genome Atlas mRNA expression data to identify isozymes that become cancer-dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the Cancer Cell Line Encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase 1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line- and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities. SIGNIFICANCE: This study exploits the loss of metabolic isozyme diversity common in cancer and reveals a rich pool of potential therapeutic targets that will allow the repurposing of existing inhibitors for anticancer therapy. See related commentary by Kehinde and Parker, p. 1695.

Optimal Management for Residual Disease Following Neoadjuvant Systemic Therapy.

OPINION STATEMENT: Treatment sequencing in early-stage breast cancer has significantly evolved in recent years, particularly in the triple negative (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive subsets. Instead of surgery first followed by chemotherapy, several clinical trials showed benefits to administering systemic chemotherapy (and HER2-targeted therapies) prior to surgery. These benefits include more accurate prognostic estimates based on the extent of residual cancer that can also guide adjuvant treatment, and frequent tumor downstaging that can lead to smaller surgeries in patients with large tumors at diagnosis. Patients with extensive invasive residual cancer after neoadjuvant therapy are at high risk for disease recurrence, and two pivotal clinical trials, CREATE-X and KATHERINE, demonstrated improved recurrence free survival with adjuvant capecitabine and ado-trastuzumab-emtansine (T-DM1) in TNBC and HER2-positive residual cancers, respectively. Patients who achieve pathologic complete response (pCR) have excellent long-term disease-free survival regardless of what chemotherapy regimen induced this favorable response. This allows escalation or de-escalation of adjuvant therapy: patients who achieved pCR could be spared further chemotherapy, while those with residual cancer could receive additional chemotherapy postoperatively. Ongoing clinical trials are testing this strategy (CompassHER2-pCR: NCT04266249). pCR also provides an opportunity to assess de-escalation of locoregional therapies. Currently, for patients with residual disease in the lymph nodes (ypN+), radiation therapy entails coverage of the undissected axilla, and may include supra/infraclavicular/internal mammary nodes in addition to the whole breast or chest wall, depending on the type of surgery. Ongoing trials are testing the safety of omitting post-mastectomy breast and post-lumpectomy nodal irradiation (NCT01872975) as well as omitting axillary lymph node dissection (NCT01901094) in the setting of pCR. Additionally, evolving technologies such as minimal residual disease (MRD) monitoring in the blood during follow-up may allow early intervention with "second-line systemic adjuvant therapy" for patients with molecular relapse which might prevent impending clinical relapse.

Disease Progression in Children With Perinatal Human Immunodeficiency Virus Correlates With Increased PD-1+ CD8 T Cells That Coexpress Multiple Immune Checkpoints.

BACKGROUND: PD-1 marks exhausted T cells, with weak effector functions. Adults living with human immunodeficiency virus (HIV) have increased levels of PD-1+ CD8 T cells that correlate with HIV disease progression, yet little is known about the role of PD-1+ CD8 T cells in children with perinatal HIV. METHODS: We enrolled 76 Kenyan children with perinatal HIV and 43 children who were HIV unexposed and quantified PD-1 levels on CD8 T cells; their coexpression with immune checkpoints (ICs) 2B4, CD160, and TIM3; correlates with immune activation and HIV disease progression; and HIV-specific and -nonspecific proliferative responses. RESULTS: PD-1+ CD8 T-cell frequencies are elevated in children with perinatal HIV and associated with disease progression. The majority of PD-1+ CD8 T cells coexpress additional ICs. ART initiation lowers total PD-1 levels and coexpression of multiple ICs. The frequency of PD-1+2B4+CD160+TIM3- in PD-1+ CD8 T cells predicts weaker HIV-specific proliferative responses, suggesting that this subset is functionally exhausted. CONCLUSIONS: Children with perinatal HIV have high levels of PD-1+ CD8 T cells that are a heterogeneous population differentially coexpressing multiple ICs. Understanding the complex interplay of ICs is essential to guide the development of PD-1-directed immunotherapies for pediatric HIV remission and cure.

Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer.

The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I-III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30-57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain-Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38-0.71) and 32% (95% CI: 0.12-0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.

Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancers.

Important results are emerging from clinical trials showing that surgery followed by chemotherapy might not be the optimal strategy to maximise a patient's chance of survival from triple-negative or HER2-positive breast cancers. Administering chemotherapy before surgery provides an opportunity to directly observe the efficacy of a particular chemotherapy regimen. Patients who have extensive residual invasive cancer after neoadjuvant chemotherapy are at a high risk of recurrence for metastatic disease, which, in turn, make these patients ideal candidates for clinical trials. Two important clinical trials, CREATE-X (UMIN000000843) and KATHERINE (NCT01772472), have shown improved disease-free survival with postoperative capecitabine and ado-trastuzumab emtansine in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy. The opportunity for residual-disease guided therapy, as observed in these trials, is lost when patients undergo surgery first. In this Personal View, we discuss the clinical implications of the CREATE-X and KATHERINE trials and place them into context with other developments in the adjuvant setting of early-stage breast cancer. We suggest that neoadjuvant systemic therapy should be considered as the new standard of care for HER2-positive and oestrogen receptor negative breast cancer, even for patients who present with operable (T1 or T2) disease.