SERENA-6 interpretation and clinical implications: intercepting endocrine resistance in metastatic breast cancer

Introduction

In patients treated with first-line AI plus CDK4/6 inhibitor, SERENA-6 showed the benefit of switching from an aromatase inhibitor to the oral SERD camizestrant upon detection of an emerging ESR1 mutation, before disease progression. While this adaptive oncology approach has shown key benefits for patients, the integration of emerging ctDNA targets into treatment decisions has been questioned. Here, we provide further clarification on several aspects of this clinically relevant discussion.

Advancing new strategies to monitor and treat metastatic cancers is a major goal in medical oncology that continues to evolve with emerging scientific insights. Advances in radiologic imaging have improved our ability to detect and measure tumor progression, from conventional X-ray studies to functional imaging with PET/CT. In parallel, molecular techniques now enable longitudinal monitoring of circulating tumor DNA (ctDNA), allowing assessment of tumor genomic evolution. Among recently identified targets, ESR1 mutations (ESR1m) are a specific marker of resistance to aromatase inhibitors (AI) in hormone receptor–positive (HR+) metastatic breast cancer (mBC), typically emerging under AI pressure. Following the proof-of-concept PADA-1 trial¹, SERENA-6 was designed as the first global, randomized, double-blind registration study to evaluate switching from an AI to the oral SERD camizestrant upon detection of ESR1m in patients with HR+ mBC receiving first-line AI plus CDK4/6 inhibitor therapy². This strategy aims to prolong first-line control through targeted intervention before clinical progression, which may be relevant in the recent context of another trial using an oral SERD in an untargeted first-line setting for all patients failing to meet its endpoint³. In tumors that escaped cell-cycle arrest, intervening at molecular resistance -before clonal dominance and diversification- may increase the likelihood of durable disease control, making early ESR1m targeting a proactive evolutionary strategy^4–7. Unlike approaches based on genomic alterations present since the early oncogenesis (such as TP53 or PIK3CA mutations), SERENA-6 tracks a resistance alteration that both drives endocrine failure and remains targetable with oral SERDs. Switching from an AI to a SERD aims to restore endocrine efficacy in the presence of ESR1m while maintaining CDK4/6 inhibition, particularly since some ESR1m may also contribute to resistance to CDK4/6i⁸.

The adoption of new technologies is known to follow a bell-shaped curve⁹. While initial results from SERENA-6¹⁰ have been described by some as the future of precision oncology¹¹, the integration of dynamic ctDNA changes into cancer treatment has been questioned¹². In this context, some aspects of this far-ranging and clinically relevant discussion warrant further clarification:

Does the SERENA-6 trial demonstrate the benefit of camizestrant in the clinical context of the study?

The design of the randomized, double-blind, placebo-controlled SERENA-6 trial has been previously published (Fig. 1²). Patients with HR+ mBC receiving first-line AI and CDK4/6i therapy who developed ESR1m without synchronous clinical disease progression were randomized to continue the standard of care (AI and CDK4/6i, unchanged, with a placebo for camizestrant) versus, in the experimental arm, to switch from the AI to camizestrant with continuation of the same CDK4/6i (with an AI placebo). Notably, camizestrant has shown notable activity against ESR1m in a phase 1 study¹³ and superiority to fulvestrant in a phase 2 trial¹⁴. Results from the second analysis of SERENA-6¹⁵, summarized in Table 1, are, in our view, compelling in demonstrating the clinical benefit of switching to an oral SERD, camizestrant, at the time of ESR1m emergence.

Fig. 1. SERENA-6 design, objectives and patient flow.

The crude estimate of the proportion of patients with emergent ESR1m in SERENA-6 is 42% (calculated as 548 patients with a positive test/(number of patients tested for ESR1m [n = 3256]—number of patients still ongoing in surveillance when screening closed [n = 1949]). Post-progression treatment allocation, pooled across arms, was obtained from the 2025 interim ¹⁰ analysis and will be updated in future communications.

Table 1.

SERENA-6 results

Endpoint	AI+CDK4/6i N = 158 patients	Camizestrant +CDK4/6i N = 157 patients	HR (95%CI) p value if available
Median progression-free survival, months (95% CI)	9.2 (7.2–9.7) [115 events]	16.6 (14.7–19.4) [90 events]	0.46 (0.34–0.62) p < 0.00001
Median time to deterioration in GHS/QoL, months (95% CI)	8.3 (2.8–26.7) [49/155 events]	23.0 (17.4–NC) [37/155 events]	0.49 (0.31–0.77)
Time to first subsequent therapy	ND	ND	0.47 (0.35–0.62)
Median progression-free survival 2, months (95% CI)	19.4 (17.8–21.4) [71 events]	25.7 (20.3–28.9) [62 events]	0.56 (0.39–0.80) p = 0.00153a
Time to second subsequent therapy	ND	ND	0.57 (0.40–0.81)
Median chemotherapy-free survival, months (95% CI)	18.7 (16.7–24.7) [76 events]	22.7 (20.3–31.5) [66 events]	0.69 (0.49–0.97)
Overall survival	N/A (immature) [35 events]	N/A (immature) [34 events]	0.92 (0.57–1.48)

Results displayed are those from the second data cut-off (DCO) June 30, 2025¹⁵.

GHS/QoL global health status/quality of life, ND not disclosed in the DCO2 presentation, HR hazard ratio, N/A not available, NC not calculable.

^aThreshold for significance at interim analysis for PFS2: p = 0.0001.

The primary endpoint was progression-free survival (PFS), measured from the time of randomization (at ESR1m emergence during first-line treatment) until the first progression or death. Extending first-line PFS by introducing a new treatment during ongoing therapy is not a new approach, with many registration trials having used the same PFS endpoint as in SERENA-6: recent examples include the PATINA and Her2CLIMB-05 trials, which introduced first-line maintenance therapy for patients with HER2+ mBC^16,17. The two only distinctions between classical maintenance trials and SERENA-6 lie in (i) the event triggering the switch: a somewhat arbitrary predefined chronological point in the patient’s treatment course (as in PATINA and Her2CLIMB-05) versus a personalized approach using ctDNA in SERENA-6, to optimize the timing of the switch to maintenance therapy; By relying on molecular triggers rather than predefined time points, the design of SERENA‑6 is arguably more rigorous than the calendar‑based approaches used in maintenance trials. (ii) the size of the target population. In this adaptive strategy, not all patients receive maintenance or treatment intensification, but rather, only the molecularly-selected subgroup of patients who harbor a highly specific predictive biomarker (i.e., ESR1m) undergoes modification of the endocrine therapy backbone. This biologic enrichment approach limits exposure to an additional therapy to those most likely to benefit, thereby reducing unnecessary toxicity and minimizing overtreatment associated with universal maintenance strategies. In this context, ctDNA-guided adaptation represents not only a biologically rational model but also a clinically more sustainable precision-based framework for treatment optimization.

A criticism of the study has been an “absence of crossover” to a SERD in the control arm. Treatment at progression was actually left to the investigators’ discretion, in line with the latest guidelines, with the possibility of unblinding. Several clinical and methodological arguments argue against including a crossover in the standard arm. First, an optional cross-over after progression was offered in PADA-1 and resulted in a short PFS (mPFS 3.5 months), numerically shorter than with fulvestrant used before progression. Second, SERENA-6 was initiated before phase 3 results of second-line oral SERD trials (EMERALD, EMBER-3¹⁸) and their approvals, with neither elacestrant nor imlunestrant showing an overall survival (OS) benefit. Also, multiple treatment options are available in the second-line setting. These include endocrine therapy-based combinations for patients with somatic PI3K pathway alterations, PARP inhibitors for patients harboring BRCA1/2 or PALB2 mutations, and chemotherapy (and most recently, antibody-drug conjugates, ADCs) for patients with a high burden of visceral disease and/or symptomatic disease requiring a more rapid therapeutic response. It would have been highly questionable and of borderline ethical acceptability to design a trial with a mandatory crossover for all patients to an unproven therapy at progression (i.e., a trial in which 100% of patients allocated to the standard arm must receive camizestrant +/− continuation of the same CDK4/6i at disease progression). In addition, crossover to camizestrant would have also prevented the study from assessing the impact of camizestrant on OS, while an adverse effect of a new agent on OS remains an important regulatory assessment. Alternatively, if crossover to a SERD in the standard arm had been part of the trial design, but as a not mandatory option (like in PADA-1), such crossover would have been introduced selection bias, as only patients with the most favorable prognosis and with access to multiple alternative options would have crossed over to second line camizestrant +/− continuation of the same CDK4/6i, This would likely make any comparison between early and delayed treatment systematically biased and difficult to interpret.

Secondary efficacy endpoints in SERENA-6 included assessment of PFS2, defined as the time from randomization to the earliest of the progression or death event after the first subsequent therapy following the initial clinical/radiologic progression. In assessing the PFS2 metric in SERENA-6, it has been suggested that the experimental arm (switch to camizestrant plus CDK4/6i before clinical progression on AI plus CDK4/6i) should be considered as two lines of therapy. PFS2 is a potentially more robust surrogate of OS than PFS, as assessment of PFS2 captures the durability of disease control over two progressions (or death). PFS2 is not a metric that counts the number of therapies received, but rather assesses the ability of a treatment change to defer the second progression; ultimately, if the second progression can be deferred for longer, the more likely it is that this will impact OS. Differences in the number of treatments received per arm are very common; among many examples, trials comparing doublets versus triplets (such as the INAVO-120 trial) inherently illustrate asymmetry in treatment exposure. Furthermore, the above criticism regarding PFS2 does not actually challenge post-progression therapies (i.e., those administered after clinical progression), but rather the treatment given immediately after randomization (before the first clinical progression). This line of reasoning implies that the treatment given in the standard arm of SERENA-6 after randomization has no efficacy, despite a median PFS in the standard arm of 9.2 months, and the fact that staying on AI plus CDK4/6i until clinical disease progression remains, to this day, the standard of care for patients with an emerging ESR1m. Finally, it is unlikely that observed PFS2 in the control arm would have been longer if more patients in SERENA-6 had received an oral SERD post progression on AI plus CDK4/6i, given the modest PFS results that have been seen in the second-line setting with these agents¹⁹.

Further follow-up to assess mature PFS2 and OS data will complement the already available results.

What clinical questions can registration drug trials answer?

If oral SERDs are approved for use both before and after clinical disease progression on AI plus CDK4/6i therapy, determining how to prioritize this interception approach compared with the currently conventional strategy, i.e., waiting for clinical disease progression and then determining whether oral SERDs are an acceptable treatment option, will be an important future consideration. SERENA-6 was a registrational study designed to assess the benefit of switching to camizestrant upon detection of emergent ESR1m during first-line therapy compared with continuing the standard of care. SERENA-6 was not designed to address the distinct clinical question of optimal timing of oral SERD therapy, and the hazard ratios reported in SERENA-6 cannot be compared with those from trials exploring novel oral SERD regimens in the second-line setting. Trials that assess optimal sequencing of therapies remain a highly important academic and clinical priority, but, to date, prior first-line registration trials have not addressed this issue. For example, the registrational trials of first-line CDK4/6i in HR+ mBC, first-line trastuzumab deruxtecan in HER2-low mBC, and first-line maintenance therapy with tucatinib in HER2-positive mBC did not have second-line cross-over to the investigational therapy in their designs, and thus did not assess optimal timing of therapy. We strongly endorse the need to design trials that assess the impact of treatment sequence and timing of therapy on OS. Such trials should ideally follow registrational trials; however, the SONIA trial illustrates the challenges of conducting these studies in a way that meaningfully impacts clinical practice²⁰. Sequencing trials are operationally complex and time‑consuming, and frequently read out after the therapeutic landscape has evolved. This is especially relevant in the second‑line setting, after disease progression, where the rapid emergence of new targeted therapies may render single‑agent oral SERDs (±continuation of the same CDK4/6 inhibitor) suboptimal, much like second line single‑agent fulvestrant in the SONIA trial.

What can be learned from this new ctDNA monitoring strategy?

Overall, the advantages of the SERENA-6 approach for patients with HR+ HER2− mBC are supported by several observations.

First, the impact of switching to camizestrant on quality of life²¹ is impressive, especially since the switch extends the durability of the best-tolerated treatment for mBC that any patient in this population is likely to receive. A significant delay in time to deterioration in global quality of life was actually reported in patients changing to oral SERD: in the standard arm, patients experienced an early deterioration in quality of life, likely reflecting the onset of clinical symptoms associated with impending subclinical tumor progression, such as pain or shortness of breath; in the investigational arm, this deterioration was substantially delayed by changing to the oral SERD. These quality of life data are particularly meaningful given that the QLQ-C30 scale is not a sensitive instrument, that the use of SERD after clinical progression has not demonstrated a clear quality-of-life benefit, and because of the randomized, double-blind design of the trial. Future research will help decipher who, among the first-line patients, are the ones most likely to experience symptoms before or at clinical progression and who could most benefit from an early treatment switch.

Second, data from clinical trials and real-world studies have identified that approximately 10–15% of patients never receive second-line therapy after first-line progression^22–24, and an additional proportion of patients require second-line chemotherapy or antibody-drug conjugate therapy due to aggressive and clinically concerning disease. Such patients may miss the potential benefit associated with targeting ESR1m with an oral SERD.

Third, and related to the above point, the populations studied in SERENA-6 and in second-/third-line trials are distinct. The latter trials were conducted in pretreated patients for whom fulvestrant or AI monotherapy in the control arm was considered acceptable at the time and enrolled a subpopulation for whom combination therapy or chemotherapy were not medically necessary. In contrast, the first-line population eligible for ctDNA monitoring in SERENA-6 was much broader, suggesting that the benefits of this approach (including the reported improvement in chemotherapy-free survival) may apply to a larger proportion of the HR+ mBC population. Many patients are not considered to be suitable candidates for oral SERD monotherapy following progression on first-line CDK4/6i plus AI therapy due to a high disease burden and a high risk of early treatment failure, which is common, even among patients whose disease progresses after more than 12 months on first-line therapy. In contrast, by monitoring patients who do not have overt clinical progression, the SERENA-6 approach offers almost all patients who develop ESR1m the chance to benefit from an oral SERD.

While ctDNA testing is currently recommended in guidelines to detect ESR1m at the time of clinical progression, the SERENA-6 approach introduces more frequent testing, focused on ESR1m. The logistics and cost of ESR1m monitoring may be legitimate obstacles to implementation; however, another proposed concern, the risk of increased testing anxiety, is not likely to negatively impact patients, in our opinion. First, ESR1m testing can be performed at the time of routine imaging and laboratory assessments, reducing complexity, and disclosure of a newly detected ESR1m can occur when patients have stable disease, without clinical progression. Most importantly, the results are actionable as switching from an AI to camizestrant improves outcomes. In the experience of the PADA-1 and SERENA-6 investigators, there was minimal incremental patient stress related to ESR1m monitoring. Furthermore, our clinical observations suggest that many patients live a nearly normal life while on first-line therapy, and that the first clinical progression is often a psychologically challenging reminder that cancer control will not be indefinite -an observation in favor of implementing ESR1m monitoring. Of note, in both PADA-1 and SERENA-6 trials, the discontinuation of ESR1m screening when the target number of randomized patients was reached accounts for the seemingly lower observed incidence of ESR1m: a cumulative incidence of approximately 40% would likely have been observed if all enrolled patients had continued testing (see Fig. 1 caption for details). Future research may better clarify the optimal timing of initiation of ESR1m monitoring to maximize mutation detection, minimize unnecessary testing, and characterize any distress associated with it.

To conclude, by leveraging molecular monitoring to guide timely treatment adaptation, SERENA-6 introduces a pragmatic and individualized approach to prolong first-line disease control in HR+ mBC. We acknowledge the current lack of additional markers to identify which patients benefit more from this type of early intervention, and expect that future analyses of the rich SERENA-6 dataset will help elucidate this important question. The collective evidence suggests that this approach benefits patients, delays chemotherapy, and safeguards quality of life. There were a few downsides for patients, as camizestrant was very well tolerated, with a very low discontinuation rate due to adverse effects.

At a higher level, PADA-1 and SERENA-6 exemplify a shift from reactive to “anticipatory adaptive oncology”, where molecular surveillance informs timely therapeutic adaptation before overt clinical failure. We are confident that evolution-informed strategies based on ctDNA monitoring will continue to expand and that the benefits to patients observed with molecularly guided treatment may extend beyond oral SERDs and ESR1-mutant breast cancer to other agents and tumor types.

Author contributions

F.-C.B. conceived the manuscript, led the project, and wrote the manuscript. L.S. contributed to the technical preparation of the manuscript. F.-C.B., C.B., G.B., A.M.B., S.C., J.C., M.C., G.C., S.D., P.A.F., L.G., A.G., M.I., H.I., W.J., E.L., K.K., C.X.M., E.L.M., A.J.M., J.A.M., J.O., Y.H.P., J.P., P.R., S.S., J.L.S., L.S., P.T., S.A.W., G.W., and N.A.T. contributed to the interpretation of the data and critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript.

Competing interests

F.-C.B. reports research funding from GE Healthcare, Menarini Silicon Biosystems, Merck KGaA, MSD, Natera, Novartis, Personalis, Pfizer, Prolynx, Roche, SAGA Dx, and Tempus; advisory board participation with AstraZeneca, Carrick, Daiichi-Sankyo, Hengrui, Inatherys, Eli Lilly, Menarini Silicon Biosystems, Novartis, Pfizer, Relay Therapeutics, Roche, and Tempus; speaker honoraria from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Novartis, and Roche; and travel support from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Novartis, Pfizer, and Roche. C.B. reports institutional research funding from multiple industry partners including Amgen, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Regeneron, Roche/Genentech, Seagen, Servier, and Taiho, as well as academic research projects with CPO, PUCRS, LACOG, and GBECAM; consulting or advisory roles, travel support and presentation honoraria from Adium, Novartis, Pfizer, Roche/Genentech, MSD, AstraZeneca, Eli Lilly, Daiichi Sankyo, and Gilead; and stock ownership in Thummi, MEDSir, and CPO. G.B. reports personal fees for consultancy, advisory boards, lectures or travel support from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche, MSD, Gilead, Menarini, Exact Sciences, Seagen, Helsinn, Takeda, and Tethis; institutional research grants from Gilead; and membership of the SERENA-6 Steering Committee. A.M.B. reports consulting roles with AstraZeneca, Pfizer, Novartis, Eli Lilly, Genentech/Roche, Daiichi Sankyo, Merck, Agendia, Puma Biotechnology, Gilead, BriaCell, and Celcuity; research support from Agendia; and stock options in Celcuity and Ataraxis. S.C. reports honoraria for lectures from Novartis, Hoffmann-La Roche, Pfizer, Eli Lilly, AstraZeneca, Gilead, Merck, Daiichi Sankyo, and Exact Sciences; and institutional research grants to BC Cancer from Novartis, Hoffmann-La Roche, Pfizer, Exact Sciences, AstraZeneca, Genentech, Merck, Sanofi, LOXO Oncology, Eli Lilly, Daiichi Sankyo, and Gilead.J.C. reports consulting or advisory roles for Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, BridgeBio, BioNTech, Biocon, Circle Pharma, Delcath Systems, Hexagon Bio, Bliss Biopharmaceutical, and Relay Therapeutics; honoraria from Roche, Novartis, Eisai, Pfizer, Eli Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Gilead, Stemline Therapeutics, and Zuellig Pharma; institutional research funding from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GmbH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, IQVIA, and Queen Mary University of London; stock ownership in MAJ3 Capital, and Leuko (relative); and patents issued and licensed as previously described. M.C. reports consulting fees from AstraZeneca, Celcuity, Menarini-Stemline, Repare Therapeutics, Olaris, BriaCell, Datar Cancer Genetics, and Eli Lilly; honoraria from Pfizer, AstraZeneca, Merck, Iylon, and Menarini-Silicon Biosystems; and research funding from AstraZeneca and Celcuity. G.C. reports consulting fees from Bristol Myers Squibb, Roche, Pfizer, Novartis, Eli Lilly, AstraZeneca, Daiichi Sankyo, Merck, Seagen, Ellipsis, Gilead, and Menarini; honoraria for lectures or presentations from Eli Lilly, Pfizer, Relay Therapeutics, Gilead and Novartis; travel support from Daiichi Sankyo; and research grants from Merck. S.D. reports honoraria from AstraZeneca, Eli Lilly, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Firebird, NewBridge Pharmaceuticals, AbbVie, and Astellas. P.A.F. reports consulting or advisory roles with AstraZeneca, Novartis, Pfizer, Roche, Daiichi Sankyo, Eli Lilly, Amgen, Boehringer Ingelheim, Celgene, Eisai, MSD, Nanostring, Pierre Fabre, Puma Biotechnology, Seattle Genetics, Tesaro, and Genentech; and institutional research support from several of these companies. L.G. reports consulting and advisory roles for AstraZeneca, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Incyte, Novartis, Pfizer, Merck Sharp & Dohme, Menarini Stemline, AbbVie, and Gilead; research funding from the Gilead Foundation, Guardant Health, and AstraZeneca; and travel support from Menarini Stemline, Novartis, Gilead, and Roche. A.G. reports advisory board roles for Pfizer, Eli Lilly, Novartis, Guardant Health, and Araris; and travel support from Totus Medicine and Pfizer. M.I. reports consulting roles for Seattle Genetics, Daiichi Sankyo, AstraZeneca, Menarini Stemline, Gilead Sciences, Novartis, Pfizer, and Rejuveron Senescence Therapeutics; institutional research support from Roche, Inivata Inc., and Natera Inc., unrelated to the present work; and uncompensated roles with the European Organisation for Research and Treatment of Cancer (EORTC). H.I. reports institutional grants or contracts from Chugai, Daiichi Sankyo, AstraZeneca, MSD, and Novartis; consulting fees from Daiichi Sankyo, Chugai, AstraZeneca, Eli Lilly, MSD, Pfizer, Gilead, and CMIC; and honoraria for lectures or presentations from Chugai, AstraZeneca, Eli Lilly, MSD, Pfizer, Gilead, and Myriad Genetics. W.J. reports research grants and honoraria from AstraZeneca, Celgene, Chugai, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, GlaxoSmithKline, Guardant Health, Janssen, Eli Lilly, Menarini Stemline, Merck Sharp & Dohme, NeoGenomics, Novartis, Pfizer, Roche, Sanofi-Aventis, and Seagen. E.L. reports institutional advisory board roles for AstraZeneca, Gilead, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche; institutional research funding from Novartis, Pfizer, and Ellipses; steering committee roles for AstraZeneca, Eli Lilly, Novartis, and Roche (no financial interest); royalties related to venetoclax from the Walter and Eliza Hall Institute; and leadership roles with Breast Cancer Trials Australia, Garvan Institute of Medical Research, St Vincent’s Hospital Sydney, and the University of New South Wales. K.K. reports advisory board roles for Genentech/Roche, Gilead, Seattle Genetics, AstraZeneca, Daiichi Sankyo, Puma Biotechnology, Mersana, Menarini Silicon Biosystems, Myovant Sciences, Merck, Eli Lilly, Pfizer, Novartis, ProteinQure, bioTheranostics, Regor, Relay Therapeutics, Bicycle Therapeutics, RayzeBio, and Jazz Pharmaceuticals; and spouse employment with EQRx (prior employee) and ADC Therapeutics. C.X.M. reports consulting fees from Puma Biotechnology, Pathlight, Genentech, Biovica, AstraZeneca, Tempus, Bayer, FoRx Therapeutics, Delphi Diagnostics, Eli Lilly, Novartis, Stemline, and Pfizer; and research funding from Pfizer. E.L.M. reports consulting roles with AstraZeneca, Genentech, Novartis, Eli Lilly, and Aktis. A.J.M. reports consulting roles with BostonGene, GE HealthCare, AstraZeneca, Aptitude Health, PreludeDX, Community Health Media, Agendia, and Stemline; research support from Bristol Myers Squibb, Summit Therapeutics, and Eli Lilly; honoraria from Novartis, Puma Biotechnology, Gilead, Pfizer, OMNI Health, DAVA Oncology, MJH, and Roundtable Oncology; steering committee participation with AstraZeneca and Novartis; and service as Scientific Advisory Board Chair of the Lobular Breast Cancer Alliance. J.O. reports honoraria for consulting or advisory board participation from Aadi Bioscience, Agendia, Amgen, Aptitude Health, AstraZeneca, BioNTech, Bristol Myers Squibb, Daiichi Sankyo, Duality, Eisai, Eli Lilly, Ellipses, Exact Sciences, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, Hibercell, Jazz Pharmaceuticals, Johnson & Johnson, Menarini Stemline, Merck, Mersana, Natera, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, Puma Biotechnology, RayzeBio, Roche, Sanofi, Seagen, Stemline Therapeutics, Summit Therapeutics, Tempus, and TerSera Therapeutics. Y.H.P. reports research funding from MSD, AstraZeneca, Pfizer, Gencurix, Roche, Inocras, and Novartis; consulting or advisory roles with AstraZeneca, MSD, Pfizer, Eisai, Eli Lilly, Roche, Gilead, Daiichi Sankyo, Menarini, Everest Medicines, and Novartis; speaker honoraria from AstraZeneca, MSD, Pfizer, Roche, Eli Lilly, Daiichi Sankyo, Novartis, Gilead, and Helsinn; travel support from Gilead, AstraZeneca, and Pfizer; advisory board participation with AstraZeneca, Menarini, Pfizer, Novartis, Roche, Daiichi Sankyo, and Helsinn; and receipt of materials or other services from Dong-A ST, Sanofi, Roche, and Pfizer. J.P. reports research grants to IBIMA from AstraZeneca and Roche; personal fees for advisory board or speaker roles from AstraZeneca, Gilead, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Stemline Therapeutics; and travel support from AstraZeneca, Gilead, Novartis, and Pfizer. P.R. reports institutional research funding from Grail, Novartis, AstraZeneca, Invitae, bioTheranostics, Tempus, NeoGenomics, Guardant Health, Personalis, Myriad Genetics, Foresight Diagnostics, Natera, Biodesix, SAGA Diagnostics, SOPHiA Genetics, Haystack, and Roche; and consulting or advisory board roles and honoraria from Novartis, AstraZeneca, Eli Lilly/Loxo Oncology, Stemline Therapeutics, Prelude Therapeutics, NeoGenomics, Regor Pharmaceuticals, SAGA Diagnostics, SOPHiA Genetics, Tempus, Myriad Genetics, Foresight Diagnostics, Natera, Pathos AI, and BioNTech. S.S. reports research funding from Alterome, Iambic, Ensem, Loxo Oncology, Seagen, Relay Therapeutics, Sermonix, Eli Lilly, AstraZeneca, DSI, and Stemline/Menarini; and consulting or advisory board roles for Eli Lilly, AstraZeneca, Gilead, Sermonix, Seagen, Pfizer, Novartis, and Daiichi Sankyo. P.T. reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eli Lilly, Gilead, Genentech/Roche, Novartis, Menarini/Stemline, Merck, and Sanofi. S.A.W. reports consulting and advisory board roles with Foundation Medicine, Veracyte, Hologic, Eli Lilly, Biovica, Pfizer, Arvinas, Puma Biotechnology, Novartis, AstraZeneca, Genentech, Regor Therapeutics, Stemline/Menarini, Gilead, Celcuity, Precede Biosciences, Halda Therapeutics, and Boundless Bio; educational or speaking activities for Eli Lilly, Guardant Health, and 2ndMD; and institutional research support from Genentech, Eli Lilly, Pfizer, Arvinas, Nuvation Bio, Regor Therapeutics, Sermonix, Puma Biotechnology, Stemline/Menarini, and Phoenix Molecular Designs. G.W. reports research funding from Astellas Pharma, AstraZeneca, Bayer, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, Roche, Takeda Pharmaceutical, Janssen, and Libbs; consulting or advisory roles for AstraZeneca, Merck & Co., Novartis, Daiichi Sankyo, and Roche; and honoraria for lectures from AstraZeneca, Merck & Co., Novartis, Pfizer, Roche, and Daiichi Sankyo. L.S. and J.L.S. declare no competing interests.