APOBEC3 mutagenesis drives therapy resistance in breast cancer.

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer 1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

The evolving landscape of metastatic HER2-positive, hormone receptor-positive Breast Cancer.

Therapeutic agents targeting Human Epidermal Growth Factor Receptor 2 (HER2) demonstrated to positively impact the prognosis of HER2-positive breast cancer. HER2-positive breast cancer can present either as hormone receptor-negative or positive, defining Triple-positive breast cancer (TPBC). TPBC demonstrate unique gene expression profiles, showing reduced HER2-driven gene expression, as recapitulated by a higher proportion of Luminal-type intrinsic subtypes. The different molecular landscape of TPBC dictates distinctive clinical features, including reduced chemotherapy sensitivity, different patterns of recurrence, and better overall prognosis. Cross-talk between HER2 and hormone receptor signaling seems to be critical to determine resistance to HER2-directed agents. Accordingly, superior outcomes have been achieved with the use of endocrine therapy, representing the first subtype-specific pharmacological intervention unique to this subgroup. Additional targeted agents capable to tackle resistance mechanisms to anti-HER2, hormone agents, or both might further improve the efficacy of treatments, such as PI3K/AKT/mTOR inhibitors, particularly in a biomarker-enriched setting, and CDK4/6-inhibitors, with preliminary data suggesting a role of PAM50 subtyping to predict higher benefits in luminal tumors. Finally, the distinct biology of triple-positive tumors may yield the rationale for considering combinations within antibody-drug conjugate regimens. Accordingly, in this review, we summarized the current evidence and rationale for considering TPBC as a different entity, in which distinct therapeutical approaches leveraging on the different biological profile of TPBC may result in superior anticancer regimens and improved patient-centric outcomes.

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis.

BACKGROUND: Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. METHODS: To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. CLINICAL REPORT AND RESULTS: We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. CONCLUSION: uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

PARP Inhibitors for Breast Cancer Treatment: A Review.

Importance: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients. Observations: This narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies. Conclusions and Relevance: Although the efficacy of PARP inhibitors is well established, many questions persist. Future research should focus on identifying predictive biomarkers and therapeutic strategies to overcome resistance. Integrating well-designed translational efforts into all clinical studies is thereby crucial to laying the groundwork for future insights from ongoing research.

Converging and evolving immuno-genomic routes toward immune escape in breast cancer.

The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.

Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations.

CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.

Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives.

Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15-20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody-drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes.

Evaluation of the Geographical Accessibility of Genome-Matched Clinical Trials on a National Experience.

BACKGROUND: Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials. MATERIAL AND METHODS: We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial. RESULTS: We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020. CONCLUSIONS: The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer.

Baseline Tumor Size as Prognostic Index in Patients With Advanced Solid Tumors Receiving Experimental Targeted Agents.

BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.

Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation.

Physiologic activation of estrogen receptor α (ERα) is mediated by estradiol (E2) binding in the ligand-binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ERα is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through expanded genetic sequencing of breast cancer patients, we identified a collection of mutations located far from H12 but nonetheless capable of promoting E2-independent transcription and breast cancer cell growth. Using machine learning and computational structure analyses, this set of mutants was inferred to act distinctly from the H12-repositioning mutants and instead was associated with conformational changes across the ERα dimer interface. Through both in vitro and in-cell assays of full-length ERα protein and isolated ligand-binding domain, we found that these mutants promoted ERα dimerization, stability, and nuclear localization. Point mutations that selectively disrupted dimerization abrogated E2-independent transcriptional activity of these dimer-promoting mutants. The results reveal a distinct mechanism for activation of ERα function through enforced receptor dimerization and suggest dimer disruption as a potential therapeutic strategy to treat ER-dependent cancers.

Nonlobular Invasive Breast Carcinomas with Biallelic Pathogenic CDH1 Somatic Alterations: A Histologic, Immunophenotypic, and Genomic Characterization.

CDH1 encodes for E-cadherin, and its loss of function is the hallmark of invasive lobular carcinoma (ILC). Albeit vanishingly rare, biallelic CDH1 alterations may be found in nonlobular breast carcinomas (NL-BCs). We sought to determine the clinicopathologic characteristics and repertoire of genetic alterations of NL-BCs harboring CDH1 biallelic genetic alterations. Analysis of 5842 breast cancers (BCs) subjected to clinical tumor-normal sequencing with an FDA-cleared multigene panel was conducted to identify BCs with biallelic CDH1 pathogenic/likely pathogenic somatic mutations lacking lobular features. The genomic profiles of NL-BCs with CDH1 biallelic genetic alterations were compared with those of ILCs and invasive ductal carcinomas (IDCs), matched by clinicopathologic characteristics. Of the 896 CDH1-altered BCs, 889 samples were excluded based on the diagnosis of invasive mixed ductal/lobular carcinoma or ILC or the detection of monoallelic CDH1 alterations. Only 7 of the 5842 (0.11%) BCs harbored biallelic CDH1 alterations and lacked lobular features. Of these, 4/7 (57%) cases were ER-positive/HER2-negative, 1/7 (14%) was ER-positive/HER2-positive, and 2/7 (29%) were ER-negative/HER2-negative. In total, 5/7 (71%) were of Nottingham grade 2, and 2/7 (29%) were of grade 3. The NL-BCs with CDH1 biallelic genetic alterations included a mucinous carcinoma (n = 1), IDCs with focal nested growth (n = 2), IDC with solid papillary (n = 1) or apocrine (n = 2) features, and an IDC of no special type (NST; n = 1). E-cadherin expression, as detected by immunohistochemistry, was absent (3/5) or aberrant (discontinuous membranous/cytoplasmic/granular; 2/5). However, NL-BCs with CDH1 biallelic genetic alterations displayed recurrent genetic alterations, including TP53, PIK3CA (57%, 4/7; each), FGFR1, and NCOR1 (28%, 2/7, each) alterations. Compared with CDH1 wild-type IDC-NSTs, NL-BCs less frequently harbored GATA3 mutations (0% vs 47%, P = .03), but no significant differences were detected when compared with matched ILCs. Therefore, NL-BCs with CDH1 biallelic genetic alterations are vanishingly rare, predominantly comprise IDCs with special histologic features, and have genomic features akin to luminal B ER-positive BCs.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

The CDK4/6 inhibitors biomarker landscape: The most relevant biomarkers of response or resistance for further research and potential clinical utility.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is) in combination with Endocrine Therapy (ET) represent the standard frontline therapy for patients with Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic Breast Cancer (mBC). Clinical activity and efficacy of CDK4/6is-based therapies have been proven both in the endocrine sensitive and resistant settings. Therapy resistance eventually underpins clinical progression to any CDK4/6is-based therapies, yet there is a lack of validated molecular biomarkers predictive of either intrinsic or acquired resistance to CDK4/6is in clinical practice. As the "post-CDK4/6is" landscape for the management of HR-positive/HER2-negative mBC is rapidly evolving with the introduction of novel therapies, there is an urgent need for the definition of clinically relevant molecular biomarkers of intrinsic/acquired resistance mechanisms to CDK4/6is. This narrative review outlines the role of currently approved CDK4/6is-based therapies, describes the most relevant molecular biomarkers of CDK4/6is-resistance, and ultimately provides a perspective on the clinical and research scenario.

Clinicopathological features and survival outcomes of luminal-like breast tumors with estrogen receptor loss at metastatic recurrence: A case-control study.

INTRODUCTION: Estrogen receptor (ER) loss at metastatic relapse occurs in up to 20% of luminal-like primary breast tumors. Data about clinicopathological features associated with ER loss and its prognostic significance are limited. METHODS: In a nested-case-control study, we compared clinicopathological characteristics and clinical outcomes between a cohort of 51 patients with primary ER+ /HER2- and paired triple-negative metastasis (LUM-TN) and two control cohorts of paired early-metastatic ER+ /HER2- (LUM-LUM, n = 50) and triple-negative (TN-TN, n = 49) breast cancers. Stromal tumor-infiltrating lymphocytes (TILs) were assessed according to the TILs Working Group recommendations as continuous and discrete variables with cutoffs (20%, 40%). RESULTS: LUM-TN tumors had lower ER expression than LUM-LUM tumors, but lower grade and Ki67 than TN-TN cases. Median distant-metastasis free survival was similar for LUM-TN and LUM-LUM cohorts, but significantly longer than in TN-TN cases (log-rank P < 0.001). LUM-TN and TN-TN cohorts had a comparable survival from the time of metastatic recurrence, which was significantly shorter than in patients with LUM-LUM tumors (log-rank P < 0.001). High TILs were associated with worse outcomes in patients with ER loss (P < 0.001). CONCLUSIONS: Breast tumors with ER loss at metastatic relapse have intermediate features and outcomes compared with metastatic luminal-like and ab initio triple-negative tumors. Further investigation on the biological mechanisms underpinning the loss of ER expression is ongoing.

TERT promoter mutations and gene amplification in endometrial cancer.

OBJECTIVE: To assess the clinicopathologic, molecular profiles, and survival outcomes of patients with endometrial carcinomas (ECs) harboring telomerase reverse transcriptase (TERT) hotspot mutations or gene amplification. METHODS: ECs harboring somatic TERT promoter hotspot mutations or gene amplification (TERT-altered) were identified from 1944 ECs that underwent clinical tumor-normal sequencing from 08/2016-12/2021. Clinicopathologic variables, somatic mutation profiles, and survival outcomes of TERT-alt and TERT-wild-type EC were assessed. RESULTS: We identified 66 TERT-altered ECs (43 TERT-mutated and 23 TERT-amplified), representing 3% of the unselected ECs across histologic subtypes. Most TERT-altered ECs were of copy number (CN)-high/TP53abn molecular subtype (n = 40, 60%), followed by microsatellite-unstable (MSI-H) or CN-low/no specific molecular profile (NSMP)(n = 13, 20% each). TERT-amplified and TERT-mutated ECs were molecularly distinct, with TERT-amplified ECs being more genomically instable and more frequently harboring TP53 and PPP2R1A alterations (q < 0.1). Compared to TERT-wild-type ECs, TERT-altered ECs were more commonly of CN-H/TP53abn molecular subtype (31% vs 57%, p = 0.001), serous histology (10% vs 26%, p = 0.004), and were significantly enriched for TP53, CDKN2A/B, and DROSHA somatic genetic alterations (q < 0.1). Median progression-free survival was 18.7 months (95% CI 11.8-not estimable [NE]) for patients with TERT-altered EC and 80.9 months (65.8-NE) for patients with TERT-wild-type EC (HR 0.33, 95% CI 0.21-0.51, p < 0.001). Similarly, median overall survival was 46.7 months (95% CI 30-NE) for TERT-altered EC patients and not reached for TERT-wild-type EC patients (HR 0.24, 95% CI 0.13-0.44, p < 0.001). CONCLUSION: TERT-altered ECs, although rare, are enriched for CN-high/TP53abn tumors, TP53, CDKN2A/B and DROSHA somatic mutations, and independently predict worse survival outcomes.

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability.

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection.

Variant allele frequency: a decision-making tool in precision oncology?

Precision oncology requires additional predictive biomarkers for targeted therapy selection. Variant allele frequency (VAF), measuring the proportion of variant alleles within a genomic locus, provides insights into tumor clonality in somatic genomic testing, yielding a strong rationale for targeting dominant cancer cell populations. The prognostic and predictive roles of VAF have been evaluated across different studies. Yet, the absence of validated VAF thresholds and a lack of standardization between sequencing assays currently hampers its clinical utility. Therefore, analytical and clinical validation must be further examined. This Review summarizes the evidence regarding the use of VAF as a predictive biomarker and discusses challenges and opportunities for its clinical implementation as a decision-making tool for targeted therapy selection.

Clinical utility of genomic signatures for the management of early and metastatic triple-negative breast cancer.

PURPOSE OF REVIEW: This comprehensive review aims to provide timely and relevant insights into the current therapeutic landscape for triple-negative breast cancer (TNBC) and the molecular features underlying this subtype. It emphasizes the need for more reliable biomarkers to refine prognostication and optimize therapy, considering the aggressive nature of TNBC and its limited targeted treatment options. RECENT FINDINGS: The review explores the multidisciplinary management of early TNBC, which typically involves systemic chemotherapy, surgery, and radiotherapy. It highlights the emergence of immune checkpoint inhibitors (ICIs), poly(ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs) as promising therapeutic strategies for TNBC. Recent clinical trials investigating the use of ICIs in combination with chemotherapy and the approval of pembrolizumab and atezolizumab for PD-L1-positive metastatic TNBC are discussed. The efficacy of PARP inhibitors and ADCs in treating TNBC patients with specific genetic alterations is also highlighted. SUMMARY: The findings discussed in this review have significant implications for clinical practice and research in TNBC. The identification of distinct molecular subtypes through gene expression profiling has enabled a better understanding of TNBC heterogeneity and its clinical implications. This knowledge has the potential to guide treatment decisions, as different subtypes display varying responses to neoadjuvant chemotherapy. Furthermore, the review emphasizes the importance of developing reliable genomic and transcriptomic signatures as biomarkers to refine patient prognostication and optimize therapy selection in TNBC. Integrating these signatures into clinical practice may lead to more personalized treatment approaches, improving outcomes for TNBC patients.

Molecular Characterization of Endometrial Carcinomas in Black and White Patients Reveals Disparate Drivers with Therapeutic Implications.

Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark, with the highest mortality rates observed among Black patients. Here, analysis of 1,882 prospectively sequenced ECs using a clinical FDA-authorized tumor-normal panel revealed a significantly higher prevalence of high-risk histologic and molecular EC subtypes in self-identified Black (n = 259) compared with White (n = 1,623) patients. Clinically actionable alterations, including high tumor mutational burden/microsatellite instability, which confer benefit from immunotherapy, were less frequent in ECs from Black than from White patients. Ultramutated POLE molecular subtype ECs associated with favorable outcomes were rare in Black patients. Results were confirmed by genetic ancestry analysis. CCNE1 gene amplification, which is associated with aggressive clinical behavior, was more prevalent in carcinosarcomas occurring in Black than in White patients. ECs from Black and White patients display important differences in their histologic types, molecular subtypes, driver genetic alterations, and therapeutic targets. SIGNIFICANCE: Our comprehensive analysis of prospectively clinically sequenced ECs revealed significant differences in their histologic and molecular composition and in the presence of therapeutic targets in Black versus White patients. These findings emphasize the importance of incorporating diverse populations into molecular studies and clinical trials to address EC disparities. This article is featured in Selected Articles from This Issue, p. 2293.

Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma.

PURPOSE: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features. METHODS: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed. RESULTS: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD. CONCLUSION: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA-related malignancies.