Citations

4183 Background: High grade neuroendocrine neoplasms (HG-NENs) are treated with platinum doublets mirroring guidelines for small cell lung cancer (SCLC) but recurrences are common and salvage options are limited in efficacy. Cabozantinib (CABO), an inhibitor of VEGFR, MET, and TAM kinases (TYRO3, AXL, and MER) was approved by the FDA for treatment of well differentiated (WD) NENs of both pancreatic and extrapancreatic origins based on the CABINET study (Chan, NEJM 2025). However, its efficacy in the whole spectrum of HG-NEN patients including poorly differentiated disease (PDD) has not been prospectively explored. Methods: This was a single institution, Phase II study of CABO in patients with HG-NENs who had progressed on at least one prior treatment. Key inclusion/exclusion criteria were NENs of any origin except SCLC, high grade by Ki-67 of > 20% or histology consensus, ECOG of < = 1, appropriate hematological parameters and no history of bleeding or active cardiac disease. CABO was given orally starting at 60 mg po daily in 3-week cycles. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). A Simon optimal 2-stage design tested the null hypothesis that the true ORR is < = 1% at the type I error rate of 5%, resulting in projected enrollment of up to 32 total patients. Toxicities were graded according to CTCAE v5.0 and response was evaluated according to RECIST v1. Results: All patients have been accrued, with 4/32 patients still on treatment. Median age at diagnosis was 62 years and male to female ratio was 1.46. Origin of tumor was GI in 68.8% of the cases, the rest being thoracic (6.3%), prostate (6.3%) cervical (6.3%) head/neck (3.1%) and unknown (9.4%). Median Ki-67 was 55%, 11 patients had Ki-67 > 70%. Histology was WD-HG in 40% of patients and PDD in 60%. Two patients had mixed PDD/other components (MiNEN). Median PFS in evaluable patients was 4.01 months [95% CI 1.61 to 9.30] and mOS was 9.89 mo [95% CI 6.73 to 18.96]. Three patients so far (9.3%) have had partial response as best response (PDD-colon, WD-pancreas and PDD-cervical) while 19/32 (59.4%) patients have had stable disease as best response so far (disease control rate 68.8%). Five (15.6%) patients have received more than 10 treatment cycles. The three longest treated patients had WD-pancreas (23 and 17 cycles) and PDD-unknown (12 cycles). One patient had eventual resection of a metastatic site and is currently without evidence of disease. Three patients withdrew from the trial because of toxicities (shortness of breath, GI bleeding, thromboembolism). Twenty-six patients have expired. Conclusions: CABO monotherapy showed efficacy in some HG-NEN patients with not just WD but also the very aggressive PDD histology. No new side effects to the ones previously described for this agent were noted. Supported by Exelixis and a Siteman investment program grant. Clinical trial information: NCT04412629 .

3516 Background: ICIs produce durable benefit in MSI-H CRC, yet optimal treatment duration and monitoring strategies remain unclear. ctDNA enables minimally invasive assessment of molecular response during and after ICI. We evaluated real-world treatment patterns, outcomes, and longitudinal ctDNA dynamics in pts with MSI-H CRC treated with ICI. Methods: Pts with MSI-H mCRC treated with first-line ICI were identified from Natera’s Real-World Database with linked longitudinal ctDNA results (Signatera, Natera, Inc.) and commercial claims data (Forian’s Hybrid data ecosystem, CHRONOS). Overall survival (OS) was estimated using available mortality data (Veritas Data Research, Fact of Death Mortality Data Index). ctDNA status was assessed pre-ICI when available and longitudinally following ICI initiation. Outcomes included OS and time to next trmt (TTNT); ctDNA dynamics following ICI discontinuation were descriptively evaluated. Results: Among 559 pts treated with first line ICI (pembrolizumab [70.1%], ipilimumab+nivolumab [15.7%], and nivolumab [11.8%]), the median duration of ICI was 266 days. Baseline (pre-ICI) ctDNA results were available for 180 pts, including 38% who were treated with chemotherapy, and most pts (71.7%, 129/180) were ctDNA-positive (ctDNA(+)) prior to ICI initiation. Of these, 89.9% (116/129) had ctDNA-timepoints after the start of ICI, and 81.0% (94/116) achieved anytime ctDNA clearance (from ctDNA(+) to negative), while 19.0% (22/116) remained ctDNA(+). ctDNA(+) at anytime after the start of ICI (HR: 8.0, p < 0.0001) or on first result after the start of ICI (HR: 3.4, p < 0.0001) was associated with inferior OS compared ctDNA-negativity (ctDNA(-)) at these time points. Among pts whose first post-ICI test was ctDNA(+), 32% switched treatments, with a median TTNT of 302 days, compared to only 6.6% of pts (median TTNT 683 days) whose first post-ICI test was ctDNA(-). First post-ICI ctDNA status was associated with longer ICI duration (median 192 days for ctDNA(+) vs 303 days for ctDNA(-)), and ctDNA(+) was predictive of inferior OS (HR: 4.9; p < 0.001). ctDNA after the end of ICI was available for 392 patients; it was persistently negative in 77.2% (303/392), persistently positive in 12.8% (50/392), cleared after the end of ICI (positive to persistently negative) in 4.1%, and the remaining 5.9% had variable patterns (e.g. positive to negative to positive). Conclusions: In this large real-world cohort of MSI-H mCRC treated with ICI, longitudinal ctDNA dynamics strongly correlated with treatment durability, time to subsequent therapy, and OS. These findings support further evaluation of ctDNA to inform treatment duration and surveillance strategies in MSI-H mCRC.

1591 Background: The 21-gene OncotypeDX (ODX) recurrence score (RS) is the standard for chemotherapy decision-making in HR+/HER2- early breast cancer (EBC), but cost limits accessibility in resource-constrained settings. The Magee equations (MEs) use routine pathology features (Nottingham grade and IHC; ER/PR/HER2/Ki-67) to estimate RS. We performed a meta-analysis to validate MEs performance as a triage tool for ODX testing and a qualitative synthesis to identify sources of discordance, highlighting the transition toward objective digital pathology AI models. Methods: A systematic review identified validation studies comparing MEs with RS in HR+ EBC. Studies with sufficient data to construct a 2X2 contingency table were included; neoadjuvant trials were excluded. Primary outcomes were Negative Predictive Value (NPV) for identifying low-risk cases (RS <26 for the current TAILORx cutoff and RS<31 for the historical cutoff) and ODX test sparing rate (TSR). Data were pooled using random-effects models. Qualitative themes regarding interpretation variability were extracted from study results and discussion sections. Results: Thirteen studies met the inclusion criteria, representing 5396 patients in global cohorts from the USA, Mexico, Colombia, Jordan, France, Belgium, and Canada. For RS >26, Magee <18 achieved pooled NPV of 0.96 (95% CI: 0.94-0.97) and TSR 61% (95% CI:51%-69%). For RS >31, NPV increased to 0.99 (95% CI: 0.97-1.00) and TSR 52% (95% CI: 44%-59%). Pooled diagnostic performance for Magee <18 predicting RS <26 demonstrated 83% sensitivity and 71% specificity (AUC 0.81, LR+:2.53, LR-:0.28). Qualitative analysis of discordance identified: (1) Inter-observer variability: Nottingham mitotic counts and Ki-67 scoring were the primary drivers of score fluctuations. (2) IHC quantification: Variations in H-score calculation and Allred-to-H-score conversion introduced heterogeneity (3) Pre-analytical and biological factors: Inflammation and stromal proliferation occasionally inflated genomic RS; selection of non-representative blocks and intratumor heterogeneity further contributed to discordance (4) Technological solutions: Digital pathology and AI models emerge as solutions to standardize these variables. Conclusions: Magee-based triage provides a safe and cost-effective strategy for HR+ EBC risk stratification, with NPV up to 99% for excluding high-risk disease and sparing up to 61% of ODX testing. These results confirm a robust histopathological signal. Transitioning to objective digital pathomics provides a pathway to reduce manual subjectivity and democratize precision oncology globally. Pooled diagnostic accuracy of Magee equations by cutoff. Magee score and RS cutoff Number of studies Total patients Pooled NPV (95% CI) ODX test sparing rate (95% CI) Magee <18/ RS>26 8 4153 0.96 (0.94-0.97) 61% (51%-69%) Magee <18/ RS>31 5 1243 0.99 (0.97-1.00) 52% (44%-59%)

1564 Background: Adolescent and young adult (AYA) females with early-stage ER-negative and/or HER2-positive breast cancer commonly receive chemotherapy to reduce risk of recurrence. Fertility concerns, counseling, and preservation may influence chemotherapy decisions and time to chemotherapy (TTC) initiation. Methods: We surveyed AYA survivors of stage I–III premenopausal ER-negative and/or HER2-positive breast cancer treated at Kaiser Permanente Northern and Southern California (2013-2022). Fertility concerns were defined as not having completed desired family size or being unsure about having completed desired family size at diagnosis. We summarized receipt of fertility counseling, receipt of chemotherapy, and use of oocyte/embryo cryopreservation for fertility preservation (FP). Among fertility-concerned patients who received chemotherapy, TTC (days from diagnosis) was assessed separately for neoadjuvant chemotherapy (NAC) vs for adjuvant chemotherapy (AdjC). Time to NAC was natural log–transformed and modeled with multivariable log-linear regression to estimate relative differences in TTC, adjusting for stage, study site, ER, HER2, age, and diagnosis year. Results: Of 363 respondents, 197 (54%) had fertility concerns at diagnosis; 183/197 (93%) received chemotherapy, similar to 153/166 (92%) among those without concerns (p=0.7). Of the concerned chemotherapy recipients, 45 (25%) saw a fertility specialist but did not pursue FP while 55 (30%) underwent FP. For the 112 fertility-concerned NAC recipients, FP was associated with longer TTC than no fertility specialist counseling (mean=41 vs. 30 days; adjusted ratio=1.39; 95% CI 1.15–1.69), whereas fertility specialist counseling without FP was not (mean= 31 vs. 30 days, adjusted ratio=1.04; 95% CI 0.86–1.25). For the 71 fertility-concerned AdjC recipients, TTC was similar for patients who did not see a fertility specialist (mean=63 days), those who froze oocytes/embryos (mean=65 days), and those who saw a fertility specialist but did not pursue FP (mean=69 days). Conclusions: In this AYA breast cancer cohort, there was no evidence that fertility concerns led patients to decline chemotherapy. FP was associated with a modest delay in NAC initiation (<2 weeks on average). Time to chemotherapy (TTC) among 183 AYA patients with ER− and/or HER2+ breast cancer and fertility concerns. Fertility-focused care N (n=183) Neoadjuvant chemotherapy (n=112) Mean TTC, days Relative difference in TTC, adjusted ratio (95%CI) Adjuvant chemotherapy (n=71) Mean TTC, days No fertility counseling from a specialist 83 (45%) 55 (49%) 29.6 Reference 28 (39%) 62.6 Received fertility counseling from a specialist No fertility preservation 45 (25%) 28 (25%) 30.7 1.04 (0.86,1.25) 17 (24%) 68.6 Fertility preservation 55 (30%) 29 (26%) 41.2 1.39 (1.15,1.69) 26 (37%) 64.6

11177 Background: Early detection of recurrence after curative-intent treatment is a critical priority, traditional imaging often detects relapse when disease burden is high, potentially limiting treatment efficacy. ctDNA has emerged as an established prognostic biomarker for molecular residual disease (MRD) detection and early relapse. We performed a real-world meta-analysis on published datasets that utilized personalized, tumor-informed ctDNA testing to assess its performance across tumor types and clinical management approaches. Methods: Real-world studies published from December 2022 to December 2025 using the personalized, tumor-informed Signatera ctDNA assay (Natera, Inc.) were included. Eligibility required ctDNA assessment in the MRD (2–16 weeks post-surgery (histology dependent)/pre adjuvant therapy (ACT)) and/or surveillance (post-ACT/end of the MRD window if no ACT was given) settings, with outcomes stratified by ctDNA status and hazard ratios (HR) reported from univariable or time-dependent Cox regression analysis. Exclusions included: clinical trials, biobanks, metastatic disease treated with palliative intent, case reports, reviews, editorials, or commentaries. Clinical outcomes were harmonized into a composite event-free survival (EFS) endpoint (time to recurrence, progression, or death). Pooled HRs and 95% CIs were estimated using random and fixed effects models and heterogeneity between studies was assessed using the I 2 and Cochran’s Q test. Median lead time from ctDNA-positivity to radiographic or clinical recurrence was summarized when available. Results: We identified 18 eligible publications comprising 3,004 unique patients across 15 solid tumor types. During the MRD window, ctDNA positivity was associated with a significantly increased risk of an EFS event compared with ctDNA negativity (pooled HR: 8.15; 95% CI: 6.12–10.85, I 2 = 0.00%, P = 0.844, n = 13). During the surveillance window, inclusive of post-definitive treatment, ctDNA positivity conferred an even greater EFS risk (pooled HR: 18.30; 95% CI: 14.17–23.65, I 2 = 0%, P = 0.911 for heterogeneity, n = 16). Across studies, ctDNA detection during surveillance preceded radiographic or clinical recurrence by a median of 3.20 months (95% CI: 2.50-4.10, P < 0.0001, n = 10), although this varied substantially by study/tumor type (I 2 = 80.9%). Conclusions: In this pan-cancer real-world meta-analysis, ctDNA positivity assessed using a tumor-informed assay was highly prognostic following curative-intent therapy at all timepoints evaluated with low heterogeneity between studies. These findings support the broad clinical utility of tumor-informed ctDNA testing for post-treatment risk stratification and longitudinal disease monitoring across solid tumors.

1110 Background: CDK4/6 inhibitors with endocrine therapy are widely used for HR+/HER2– metastatic breast cancer (BC). While studies have shown similar progression-free outcomes across agents, overall survival (OS) data are limited. Since OS is a definitive endpoint and BMI may influence outcomes, this study examines BMI-dependent OS differences among CDK4/6 inhibitors. Methods: A retrospective cohort study was conducted using the Mayo Clinic Platform full AMC1 dataset. Postmenopausal women with BC receiving palbociclib/ribociclib/abemaciclib plus aromatase inhibitor (AI) were included. Patients with prior use of fulvestrant, anthracyclines, radiation therapy, GnRH agonists, or history of MACE, heart failure, myocardial infarction, or stroke before BC diagnosis were excluded. Patients were stratified by BMI and CDK4/6 inhibitor. The primary outcome was 5-year OS. Results: Among 1,989 patients (palbociclib: 868; ribociclib: 465; abemaciclib: 656), palbociclib was associated with significantly worse OS compared to ribociclib in BMI <25 (HR 2.91; 95% CI: 1.76–4.79; P < 0.01) and BMI ≥30 (HR 1.91; 95% CI: 1.21–3.01; P < 0.01). Compared to abemaciclib, palbociclib showed worse OS: BMI <25 (HR 1.73; P < 0.01), BMI 25–30 (HR 1.56; P < 0.01), and BMI ≥30 (HR 1.82; P < 0.01). No significant OS differences were observed between ribociclib and abemaciclib. Palbociclib patients were older, particularly in BMI <25 (Cohen's D = 0.39 vs. ribociclib; 0.27 vs. abemaciclib) and BMI ≥30 (0.28 vs. ribociclib; 0.23 vs. abemaciclib). In the BMI 25–30 group, palbociclib group was also older than ribociclib group (Cohen's D = 0.26). Conclusions: In postmenopausal BC patients on AIs and CDK4/6 inhibitors, palbociclib was associated with worse OS in BMI < 25 and BMI ≥ 30 groups, while ribociclib and abemaciclib showed similar outcomes across BMI groups. Palbociclib patients were older than those on other drugs, which may partially confound results; however, in the BMI 25–30 group, despite similar age differences, no survival difference was observed between palbociclib and ribociclib, suggesting age alone may have limited impact. These findings indicate a potential interaction between BMI and drug choice, and highlight the need for prospective studies to confirm and adjust for these variables. Limitations include the observational design and inability to perform multivariable regression analyses to adjust for confounders. Overall survival comparisons by CDK4/6 inhibitor and BMI subgroup. Comparison BMI Group Hazard Ratio (95% CI) P-value Palbociclib vs Ribociclib <25 2.91 (1.76 – 4.79) < 0.01 25 – 30 1.34 (0.87 – 2.071) 0.17 ≥30 1.91 (1.21 – 3.01) < 0.01 Palbociclib vs Abemaciclib <25 1.73 (1.29 – 2.32) < 0.01 25 – 30 1.56 (1.09 – 2.23) < 0.01 ≥30 1.82 (1.15 – 2.88) < 0.01 Ribociclib vs Abemaciclib <25 1.27 (0.81 – 1.99) 0.29 25 – 30 0.87 (0.54 – 1.43) 0.59 ≥30 1.05 (0.63 – 1.75) 0.85

10585 Background: Prior studies suggest that thyroid cancer (TC) survivors may have an elevated risk of secondary malignancies. However, whether this risk differs by TC histology, specifically with breast cancer (BC), remains unclear. We aimed to investigate the association between TC subtype—papillary thyroid carcinoma (PTC) versus medullary thyroid carcinoma (MTC)—and subsequent BC risk, adjusting for demographic factors. Methods: We conducted a retrospective cohort study using the SEER (2000–2022), including adults with a primary, microscopically confirmed PTC or MTC. Subsequent BC occurrence was defined as a binary outcome (yes/no). Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for MTC versus PTC, controlling for age (<50 vs ≥50 years), sex, and race. Stratified analyses by age and race were also performed. Stata 15 was used for statistical analyses. Results: 14,840 patients (14,563 PTC, 277 MTC) were included. MTC patients were older (mean 59.08±12.66 vs 56.16±12.98 years, p<0.001) and had a higher proportion of males (44.4% vs 29.4%, p<0.001). The overall incidence of secondary BC was lower in MTC patients (7.6% vs 22.5%, p<0.001). In unadjusted logistic regression, MTC was associated with significantly lower BC risk (OR=0.28, 95% CI: 0.18–0.44, p<0.001). After adjustment, MTC remained significantly protective (aOR=0.34, 95% CI: 0.22–0.55, p<0.001). Stratified analyses demonstrated consistent findings across age groups (<50: aOR=0.10, 95% CI: 0.03–0.42; ≥50: aOR=0.34, 95% CI: 0.21–0.54), , as well as white and Hispanic patients. Conclusions: Survivors of MTC have a substantially lower risk of developing secondary BC compared to PTC survivors. This association persists after adjustment for age, sex, and race, and is consistent across age and most racial subgroups. However, different BC types were not assessed due to limited number of BC patients among MTC survivors, and the small MTC sample size and potential survival differences between groups may affect the results. These findings highlight a possible effect of TC subtype on BC risk, suggesting the potential influence of underlying biological or genetic mechanisms. Baseline demographic characteristics of patients with papillary and medullary thyroid carcinoma. Characteristic Papillary Thyroid Carcinoma (PTC) (N=14,563) Medullary Thyroid Carcinoma (MTC) (N=277) P-value Age at Diagnosis 0.0002* Mean ± SD, years 56.16 ± 12.98 59.08 ± 12.66 Median, years 57 61 Sex, n (%) <0.001† Female 10,288 (70.6) 154 (55.6) Male 4,275 (29.4) 123 (44.4) Race, n (%) 0.015† White 10,263 (70.5) 197 (71.1) Black 921 (6.3) 15 (5.4) American Indian 77 (0.5) 1 (0.4) Asian 1,379 (9.5) 13 (4.7) Hispanic 1,903 (13.1) 50 (18.1) SD: Standard Deviation. *P-value from two-sample t-test (equal variances assumed). †P-value from chi-square test for the overall distribution across categories.

Abstract Background Accurate and efficient dose calculation is essential for online adaptive planning in proton therapy. Deep learning (DL) has shown promising dose prediction results for pencil beam scanning proton therapy (PBSPT) in recent years, but existing DL‐based dose prediction methods still suffer from limited generalizability and an inability to effectively handle outlier clinical cases. This may lead to inaccurate dose delivery to targets or excessive irradiation to organs at risk (OARs), thereby compromising the safety and efficacy of online adaptive proton therapy. Purpose To design a physics‐aware and generalizable AI‐based PBSPT dose prediction method that incorporates underlying physics to enhance generalizability, particularly in handling outlier clinical cases. Methods This study analyzed PBSPT plans of 103 prostate (93 for training and 10 for testing) and 78 lung cancer patients (68 for training and 10 for testing) from our institution, with each case comprising CT images and structure sets. Using the doses generated by our Monte Carlo‐based dose engine as the reference standard, we compared three methods: the region of interest (ROI)‐based method, the beam mask and sliding window method, and the proposed noisy probing dose method, which rapidly generates a low‐statistics dose via uniformly weighted spots on an expanded spot‐placement target volume without optimization. To evaluate the generalizability of these methods to rare treatment planning scenarios, 12 cases with uncommon beam angles or prescription doses were used to assess their performance, which was evaluated using dose‐volume histogram (DVH) indices, 3D Gamma passing rates (3%/2 mm/10%), and Dice coefficients for dose agreement, while prediction times were measured to gauge model efficiency. Results The proposed noisy probing dose method consistently outperformed the ROI‐based and beam mask baselines across all evaluated metrics, with more accurate dose agreement and superior generalizability. For DVH indices, the noisy probing dose method achieved the smallest deviation in clinical target volume (CTV) dose coverage: in prostate cancer, CTV D98 deviation was reduced by 45% (from 0.53 ± 0.22 Gy [RBE] for ROI‐based) and 29% (from 0.41 ± 0.28 Gy [RBE] for beam mask) to 0.29 ± 0.06 Gy [RBE]; in lung cancer, similar improvements were observed, with CTV D98 deviations reduced to 0.34 ± 0.12 Gy [RBE]. The 3D Gamma passing rates improved to 99.65% ± 1.15% for prostate targets and 97.04% ± 1.17% for lung targets. The dice coefficients of the 90% iso‐dose lines were also the highest with the noisy probing dose method (prostate: 0.983 ± 0.005; lung: 0.967 ± 0.01). For the 12 outlier cases, the noisy probing dose method maintained superior generalizability, yielding higher 3D Gamma passing rates (prostate targets: 96.79% ± 0.83%, OARs: 94.29% ± 1.01%; lung targets: 93.38% ± 1.34%, OARs: 93.95% ± 1.32%), demonstrating robust generalizability to rare clinical scenarios. The dose predictions for all testing cases were completed within 0.3 seconds. Conclusions A novel noisy probing dose method was proposed for PBSPT dose prediction in prostate and lung cancer patients. By embedding more proton‐specific physics, this method demonstrated an improvement in the generalizability of dose prediction.

ABSTRACT Objective Management of vestibular schwannoma (VS) remains controversial. Very small VSs represent a pivotal group: on one hand, they pose the least risk to the patient from the perspective of being small; yet, not recommending treatment may result in missing a critical window for achieving the best outcome. This debate fundamentally hinges on whether treatment improves upon the natural history of the disease. There is an unproven assumption that very small tumors behave similarly to the broader observed population. To address this central question, we conducted a multicenter retrospective review to compare the natural history of tumor growth and hearing for patients with very small VS (1–3 mm) with a referent cohort with larger tumors. Methods All patients diagnosed with sporadic VS 1–3 mm were reviewed at 3 large skull base referral centers and compared with a referent cohort of patients with tumors > 3 mm. Tumor growth‐free survival rates, treatment‐free survival rates, and rates of maintenance of class A, B, or C hearing were estimated using the Kaplan–Meier method. Results In total, 123 patients with very small VS and a referent cohort of 326 patients were studied. Seventeen patients with very small VS experienced tumor growth at a median of 3.2 years after diagnosis (IQR 2.6–5.1), demonstrating a median growth rate of 1.0 mm per year (IQR 0.9–1.8). In comparison, 167 of the patients in the referent cohort experienced tumor growth at a median of 1.7 years after diagnosis (IQR 0.8–3.1). Tumor growth‐free survival rates (95% CI, number still at risk) at 5 years after diagnosis for the 2 cohorts were 84% (75–93, 39) and 45% (40–52, 100), respectively ( p < 0.001). Six patients with very small VS underwent treatment after tumor growth at a median of 3.2 years after diagnosis (IQR 3.2–3.8), compared with 138 patients in the referent cohort at a median of 2.2 years after diagnosis (IQR 1.4–3.6). Treatment‐free survival rates (95% CI, number still at risk) at 5 years after diagnosis for the 2 cohorts were 92% (86–98, 55) and 54% (49–61, 125), respectively ( p < 0.001). Among the 105 patients with very small VS and class A, B, or C hearing at diagnosis, 3 progressed to class D. Comparatively, among the 225 patients in the referent cohort with class A, B, or C hearing at diagnosis, 70 progressed to class D at a median of 2.6 years after diagnosis (IQR 1.0–4.8). Rates of maintenance of class A, B, or C hearing (95% CI, number still at risk) at 5 years after diagnosis were 96% (92–100, 28) for patients with very small VS and 65% (57–73, 70) for the referent cohort ( p < 0.001). Conclusions The natural history of tumor growth and hearing for very small VS diverges favorably from the cumulative natural history data and provides a more appropriate benchmark to compare clinical outcomes of upfront surgery or radiosurgery for this population. At 5 years after diagnosis, 96% of very small VS maintained class A, B, or C hearing and only 8% received treatment for growth within this multicenter cohort. Cumulatively, these data substantiate initial wait‐and‐scan management via size threshold surveillance in this population. Level of Evidence 3.