Abstract
Purpose:
Multi-disciplinary molecular tumor boards (MTB) have demonstrated improved clinical outcomes in various malignancies. Sequential next-generation sequencing (NGS) is widely performed at the time of recurrence, which may lead to multiple MTB reviews. This study assessed the clinical benefit of multiple MTB reviews for sequential NGS.
Methods:
A retrospective cohort review was performed to compare patients reviewed once at a single-institution MTB and those reviewed multiple times for the same diagnosis with sequential NGS between January 2016 and December 2023. Demographics were compared, and regression and survival analysis was performed.
Results:
3702 patients were included, 3446 (91.6%) were reviewed once, and 256 (8.4%) were reviewed multiple times. Patients reviewed once had higher proportion of actionable findings (52.7% vs 44.5%, p = 0.01) compared to those reviewed multiple times at initial review. Approximately half of patients at their 2nd (47.3%) and 3rd or more (62.5%) reviews had actionable findings. Mean time on recommended targeted therapy for patients reviewed multiple times was 8.24 months (SD 9.34, range 0.07–42.4), and mean time on recommended immunotherapy was 7.02 months (SD 9.47, range 0.1–39.2). Patients with multiple MTB reviews had a 30% lower risk of death compared to those reviewed once, even after controlling for primary site, age, presence of actionable NGS findings, and stage (HR 0.7, CI 0.55–0.89, p= 0.004).
Conclusion
Sequential NGS identified actionable findings in approximately 50% of those with multiple reviews, and many patients stay on recommended therapy for at least six months. Patients with sequential NGS and multiple reviews have a survival advantage, and while this may be due to therapy sensitivity, it reflects the importance of NGS testing and usefulness of MTB in interpreting those results.
Introduction:
Precision therapy, including targeted therapy and immunotherapy, improves survival for multiple types of cancer.1–4 To identify candidates for targeted and immunotherapy, next-generation sequencing (NGS) is performed. NGS detects variants and mutations that can provide key information to physicians and patients for therapy selection.5 However, NGS findings can be complex and difficult to interpret.2, 6
With the advent of a multitude of options for precision therapy, many institutions have turned to molecular tumor boards (MTBs), which assemble a multi-disciplinary team across multiple specialties, often including oncology, surgery, pathology, pharmacy, and basic researchers. MTBs review patient cases and NGS results and recommend individual treatment and clinical trial options specific to the patient’s disease course. Implementation of MTB recommendations have been shown to improve clinical outcomes, including progression-free and overall survival, for patients who have undergone review.2, 6–8
International guidelines for certain tumor types, including lung, breast and colorectal cancers, recommend sequential NGS testing at disease progression or recurrence, especially as prior immunotherapy can lead to tumor acquired resistance.9–16 With the rise of NGS utilization from both sequential testing and improved insurance coverage for testing, more patients are undergoing multiple MTB reviews.17 Despite this, there is a paucity of research on the utility of multiple MTB reviews and sequential NGS testing.
The purpose of this study is to determine the clinical benefit of multiple MTB reviews for sequential NGS testing. The primary outcomes are overall survival and determining predictive factors for multiple MTB reviews. Secondary outcomes included (1) evaluating percent of actionable findings, (2) treatment recommendation differences between the two cohorts, (3) evaluating if recommended treatment was initiated for those undergoing multiple reviews, and (4) length of time on recommended treatment for those in the multiple review cohort.
Methods:
Study Design and Setting
This study was a retrospective cohort review comparing patients reviewed once at the University of Kentucky’s (UK) Markey Cancer Center (MCC) Molecular Tumor Board to those reviewed multiple times by the same MTB. The UK MTB includes medical and surgical oncologists, pharmacists, pathologists, and genetic counselors who review NGS results for patients at MCC and those referred from physicians across the commonwealth of Kentucky. The MTB meets twice a month to discuss referred patients and agree on recommendations. After thorough review of NGS results and the patient’s clinical history, the MTB recommends treatments based on sequencing results in the context of the patient’s diagnosis, clinical stage, and any prior therapy. Recommendations may include standard of care treatment, on- or off-label treatment, clinical trial enrollment, or germline testing. These recommendations are sent to the referring physicians via a consult letter and are also added to the electronic medical record (EMR). Referring physicians are ultimately responsible for NGS testing and treatment decisions. Information pertaining to patient demographics, diagnosis, staging, NGS sequencing results and recommendations from the MTB are also prospectively collected in an internal database (LabKey, Seattle, WA).
Patient Selection
The University of Kentucky’s Molecular Tumor Board Database, which includes information on all patients reviewed by the UK MCC MTB, was queried for all cases from January 1, 2016 to December 31, 2023. Patients were included if they were over the age of 18 years at the time of review. Patients who had been reviewed by MTB multiple times for the same primary malignancy with different NGS data evaluated each time were included in the multiple review cohort. Additionally, patients reviewed multiple times who underwent an electronic medical record (EMR) review were excluded if no record of that patient was in UK EMR or if their EMR chart indicated they were incarcerated. Patients with multiple reviews but for different primary sites were also excluded from the multiple review cohort. Results from several NGS testing assays were included, including FoundationOne® (Foundation Medicine, Inc., Cambridge, MA, USA), Caris Molecular Intelligence® (Caris Life Sciences, Irving, TX, USA), and Guardant® (Guardant Health, Inc., Redwood City, CA, USA). NGS assay choice was made by the referring physician who originally ordered the NGS testing. This study was approved by the University of Kentucky Institutional Review Board (Protocol number 89872, approved August 7, 2023) and followed Declaration of Helsinki guidelines as per US Common Rule. Informed consent was waived by the IRB for this retrospective cohort study.
Data Collection
Information including demographics, diagnosis, treatment, NGS results, and MTB recommendations were retrieved for all eligible patients from the prospectively collected UK MCC MTB database. Patients who underwent MTB review multiple times for new sequencing results had additional data collected retrospectively from the UK EMR, including whether patients received recommended treatment, time on treatment recommended by MTB, and whether the patient joined a recommended clinical trial. Time on treatment was defined as months a patient received recommended targeted or immunotherapy from the date of one review until date of next review.
The Kentucky Cancer Registry is a population-based registry for the Commonwealth of Kentucky that collects information on all cancer cases diagnosed or treated in Kentucky.18 Included patients were matched to the Kentucky Cancer Registry (KCR) for additional survival data.
Primary sites with small sample sizes were grouped. Other GI category includes gastric, esophageal, small bowel, pancreatic, and hepatobiliary cancers. Gynecologic (GYN) category includes uterine, cervical, ovarian/fallopian tube/primary peritoneal, and vulvovaginal cancers. Other category includes bone, blood, cardiac, and lymph node primary sites.
Statistical methods
Data were deidentified and analyzed using descriptive statistics, including mean and standard deviation, to summarize key characteristics of the study cohort. Demographics of those reviewed at UK MCC MTB once and those reviewed multiple times were described using Chi-square test or Fisher’s exact test depending on sample size for each variable. Multiple logistic regression analysis was performed to identify variables that predict multiple reviews. Survival analysis was performed using Cox proportional hazards model and fitted to estimate the effect of multiple reviews at MTB on survival while adjusting for other variables. The Chi-square test (or Fisher's exact test) and univariate logistic regression analysis was performed using complete case analysis, in which observations with missing data on sex, race, primary site, stage, or review findings at the initial review were excluded. All tests were two-sided. Statistical significance was considered P value less than 0.05.
Results:
Demographics
A total of 3769 patients were reviewed at the University of Kentucky Markey Cancer Center Molecular Tumor Board during the study period. After excluding those who did not meet study criteria, a total of 3702 were included in this study, with 3446 (91.6%) undergoing review once and 256 (8.4%) undergoing multiple reviews (Figure 1). Two hundred and twenty-four of the 256 patients reviewed multiple times had two reviews, while 26 patients were reviewed three times, four were reviewed four times, and two were reviewed five times.
Figure 1: Demographic Flow Chart.
Flow chart of patients reviewed at MTB and those included in the study with exclusionary criteria.
In the entire study population, the majority of patients were younger than 65 years (55.0%), female (55.2%), and self-identified as white (81.5%) (Table 1). The three most common primary tumor sites were lung (n=954, 25.8%), other gastrointestinal (GI) cancers (n=612, 16.5%), and gynecologic cancers (n=471 12.7%) (Table 1). The majority of patients reviewed at the UK MCC MTB had stage 4 disease (n=2233, 60.3%). At time of data analysis, the majority of patients reviewed were alive (n=2604, 70.3%) (Table 1).
Table 1:
Demographic comparison between those reviewed once and those reviewed multiple times at MTB
| Demographic | Total N (%) |
One review N (%) |
Multiple reviews N (%) |
P-value* |
|---|---|---|---|---|
| All patients | 3702 (100) | 3446 (91.61) | 256 (8.39) | |
| Age at first review | <.0001 | |||
| 18–64 | 2037 (55.02) | 1866 (54.15) | 171 (66.8) | |
| ≥65 | 1665 (44.98) | 1580 (45.85) | 85 (33.2) | |
| Sex | 0.04 | |||
| Male | 1656 (44.73) | 1558 (45.21) | 98 (38.28) | |
| Female | 2045 (55.24) | 1888 (54.79) | 157 (61.33) | |
| Missing | 1 (0.03) | 1 (0.39) | ||
| Race | 0.83 | |||
| Black | 166 (4.48) | 155 (4.5) | 11 (4.3) | |
| White | 3017 (81.5) | 2780 (80.67) | 237 (92.58) | |
| Asian | 31 (0.84) | 28 (0.81) | 3 (1.17) | |
| Other | 25 (0.68) | 24 (0.7) | 1 (0.39) | |
| Missing | 463 (12.5) | 459 (13.32) | 4 (1.56) | |
| Primary site | <.0001 | |||
| Head/neck cancer | 144 (3.89) | 139 (4.03) | 5 (1.95) | |
| Breast | 210 (5.67) | 183 (5.31) | 27 (10.55) | |
| Lung | 954 (25.77) | 906 (26.29) | 48 (18.75) | |
| GYN | 471 (12.72) | 428 (12.42) | 43 (16.8) | |
| Other GI | 612 (16.53) | 562 (16.31) | 50 (19.53) | |
| Colorectal/Anal | 460 (12.43) | 408 (11.84) | 52 (20.31) | |
| Connective and soft tissue | 107 (2.89) | 104 (3.02) | 3 (1.17) | |
| CNS and PNS | 100 (2.7) | 95 (2.76) | 5 (1.95) | |
| Genitourinary | 232 (6.27) | 224 (6.5) | 8 (3.13) | |
| Thyroid | 107 (2.89) | 100 (2.9) | 7 (2.73) | |
| Skin | 129 (3.48) | 127 (3.69) | 2 (0.78) | |
| Unknown Primary | 95 (2.57) | 90 (2.61) | 5 (1.95) | |
| Other | 78 (2.11) | 77 (2.23) | 1 (0.39) | |
| Missing | 3 (0.08) | 3 (0.09) | ||
| Stage | <.0001 | |||
| Stage 1 | 134 (3.62) | 127 (3.69) | 7 (2.73) | |
| Stage 2 | 174 (4.7) | 171 (4.96) | 3 (1.17) | |
| Stage 3 | 453 (12.24) | 434 (12.59) | 19 (7.42) | |
| Stage 4 | 2233 (60.32) | 2068 (60.01) | 165 (64.45) | |
| Recurrent disease | 285 (7.7) | 235 (6.82) | 50 (19.53) | |
| Missing | 423 (11.43) | 411 (11.93) | 12 (4.69) | |
| Death status (at time of database review) | 0.78 | |||
| No | 2604 (70.34) | 2422 (70.28) | 182 (71.09) | |
| Yes | 1098 (29.66) | 1024 (29.72) | 74 (28.91) |
P-value calculated by Chi-square test or Fisher exact test if sample size in cell less than 5. Missing is not included in p value calculation.
In comparing patients reviewed once to those with multiple reviews, patients with multiple reviews were more likely to be younger (66.8% under the age of 65 years vs 54.2%, p= <0.001), female (61.3% vs 54.8%, p= 0.04), diagnosed with breast (10.6% vs 5.3%), gynecologic (16.8% vs 12.4%), other GI (19.5% vs 16.3%), and colorectal cancers (20.3% vs 11.8%; p <0.0001), and have recurrent disease (19.5% vs 6.8%, p=<0.001) compared to patients who were only reviewed once (Table 1). Patients with lung (26.3% vs 18.8%), genitourinary (6.5% vs 3.1%) and head and neck cancers (4.0% vs 1.9%) were more prevalent in the one review cohort (p= <0.0001) (Table 1).
Over 17 types of NGS tests were represented, including FoundationOne®, Caris MI Profile®, and Guardant 360®. As this data set includes results dating to 2016, some of these tests are no longer available. The most common NGS test were the CARIS MI Profile (47.9% of total, 48.9% of those with one review, and 34.7% of multiple review at first review) and FoundationOne CDx® (25.2% of total, 25.1% of one review, 27.3% of those with multiple review at first review) (supplemental table 1). Eighty-one percent of all test samples were tissue-based, which remained the most common test sample for those with one review only (82.1%) and multiple review (55% at 2nd review). The UK MTB LabKey database did not have all sample types available for all patients, with 134 patients total not having sample type information available for initial review. The majority of NGS tests (96.9% of one review, 96.1% of multiple review at first review) were comprehensive tests, which uses parallel sequencing to analyze samples, compared to “hotspot” tests, which look for specific mutations, which made up less than less than 3% of tests across reviews.
Predictors of Multiple Reviews
In the regression analysis, age, primary site, and stage of disease were found to be predictors of multiple reviews at MTB (Table 2). Patients aged 18–64 years were more likely to have multiple reviews compared to patients over the age of 65 years old (OR 1.56, 95% CI 1.17–2.08, p= .003). Patients with breast (OR 4.59, 95% CI 1.7–12.4, p= .0003), GYN (OR 3.6, 95% CI 1.37–9.47, p= .003), other GI (OR 3.57, 95% CI 1.37–9.32, p=.002), and colorectal cancer (OR 4.12, 95% CI 1.59–10.71, p=.0001) were more likely to have multiple reviews compared to patients with head and neck cancer (Table 2). Patients who had recurrent disease are 4.71 times more likely to have multiple reviews compared to patients who have Stage I disease (OR 4.71, 95% CI 2.03–10.93, p< 0.001).
Table 2:
Regression Analysis Examining Predictors of Multiple Molecular Tumor Board Reviews
| Odds ratios (Multiple review compared only 1 review) | |||
|---|---|---|---|
| Point Estimate | 95% Wald Confidence Limits | p-value | |
| Age at first review | |||
| 18–64 | 1.56 | 1.17–2.08 | 0.003 |
| ≥65 (reference) | |||
| Primary site | |||
| Head/neck cancer (reference) | |||
| Breast | 4.59 | 1.7–12.42 | 0.0003 |
| Lung | 2.35 | 0.9–6.11 | 0.24 |
| GYN | 3.6 | 1.37–9.47 | 0.003 |
| Other GI | 3.57 | 1.37–9.32 | 0.002 |
| Colorectal/Anal | 4.12 | 1.59–10.71 | 0.0001 |
| Connective and soft tissue | 0.76 | 0.14–4.04 | 0.19 |
| CNS and PNS | 1.22 | 0.13–11.47 | 0.68 |
| GU | 1.28 | 0.41–4.07 | 0.34 |
| Thyroid | 2.0 | 0.58–6.87 | 0.83 |
| Skin | 0.54 | 0.1–2.9 | 0.07 |
| Unknown Primary | 2.11 | 0.54–8.26 | 0.77 |
| Other | 1.67 | 0.18–15.73 | 0.92 |
| Stage | |||
| Stage 1 (reference) | |||
| Stage 2 | 0.37 | 0.09–1.46 | 0.01 |
| Stage 3 | 0.89 | 0.36–2.19 | 0.2 |
| Stage 4 | 1.7 | 0.76–3.79 | 0.04 |
| Recurrent disease | 4.71 | 2.03–10.93 | <.0001 |
Molecular Tumor Board Outcomes
Of the 3702 patients in the overall study population, 1930 (52.1%) had an actionable finding at initial review (defined as an identified genetic finding or mutation that could be targeted with a certain treatment) (Table 3). Germline testing was recommended for 1226 (33.1%) patients, and clinical trials were recommended for 1598 (43.2%) patients. Targeted therapy was recommended for 1180 (31.9%) patients, and immunotherapy was recommended for 1093 (29.5%) patients (Table 3).
Table 3:
Molecular Tumor Board Recommendations – Patients reviewed once compared to all with multiple reviews at initial review.
| Recommendations: One review vs All multiple reviews | ||||
|---|---|---|---|---|
| Demographic | Total N (%) |
Patients reviewed only once N (%) |
Patients with multiple reviews N (%) |
P-value |
| All patients | 3702 (100) | 3446 (93.16) | 256 (6.84) | |
| Actionable Finding | 0.01 | |||
| No | 1772 (47.87) | 1630 (47.3) | 142 (55.47) | |
| Yes | 1930 (52.13) | 1816 (52.7) | 114 (44.53) | |
| Germline Testing recommended | 0.58 | |||
| No | 2476 (66.88) | 2309 (67.01) | 167 (65.23) | |
| Yes | 1226 (33.12) | 1137 (32.99) | 89 (34.77) | |
| Clinical trial recommended | 0.21 | |||
| No | 2104 (56.83) | 1949 (56.56) | 145 (56.64) | |
| Yes | 1598 (43.17) | 1497 (43.44) | 111(43.36) | |
| Targeted therapy (on or off label) | 0.02 | |||
| No | 2522 (68.13) | 2365 (68.63) | 155 (60.55) | |
| Yes | 1180 (31.87) | 1081 (31.37) | 101 (39.45) | |
| Immunotherapy (on or off label) | 0.0001 | |||
| No | 2609 (70.48) | 2400 (69.65) | 209 (81.64) | |
| Yes | 1093 (29.52) | 1046 (30.35) | 47 (18.36) | |
| TMB finding at time of initial review | 0.01 | |||
| No | 1315 (35.52) | 1225 (35.55) | 90 (35.16) | |
| Yes | 615 (16.61) | 591 (17.15) | 24 (9.37) | |
| Not actionable finding | 1772 (47.87) | 1630 (47.3) | 142 (55.47) | |
| PD-L1 finding at time of initial review | 0.01 | |||
| No | 1464 (39.55) | 1366 (39.64) | 98 (38.28) | |
| Yes | 466 (12.59) | 450 (13.06) | 16 (6.25) | |
| Not actionable finding | 1772 (47.87) | 1630 (47.3) | 142 (55.47) | |
Approximately half of those reviewed once (52.7%) and those reviewed multiple times (44.5%) had an actionable finding identified on their NGS report at initial review, which was a statistically significant difference (p= 0.01) (Table 3). Those reviewed once had significantly higher proportion of elevated tumor mutational burden (TMB) at initial review (17.1% vs 9.4%, p=0.01) as well as a higher Programmed death-ligand 1 (PD-L1) positivity (13.1% vs 6.3%, p= 0.01) compared to those reviewed multiple times at their initial review. Patients with one molecular tumor board review had a significantly higher proportion of immunotherapy recommendations (30.4% vs 18.4%, p <0.0001) compared to those reviewed multiple times (Table 3). However, those reviewed multiple times were more likely to be recommended targeted therapy (39.5.% vs 31.4%, p= 0.02) compared to those reviewed once. There was no significant difference between the cohorts with regards to germline testing or clinical trial recommendations (Table 3).
The UK EMR was reviewed for the 256 patients with multiple MTB reviews. While every patient with multiple reviews included in our cohort had an initial EMR record, not every patient received subsequent care at UK, thus full treatment information was not available for every patient with multiple reviews. Of the 102 patients reviewed multiple times with treatment records available in the UK EMR, 54.9% received the recommended treatment between review 1 and 2, and 52% received the recommended treatment between review 2 and 3.
For those with treatment information available, the mean time on treatment for patients reviewed multiple times who were recommended to receive targeted therapy was 8.24 months (SD 9.34, range 0.07–42.4). Mean time on treatment for patients reviewed multiple times who were recommended immunotherapy was 7.02 months (SD 9.47, range 0.1–39.2).
When examining those with multiple reviews, 47.3% (n=106) had an actionable finding at their 2nd review and 62.5% (n=20) had an actionable finding at their 3rd or more review. Actionable findings were more common in lung (n= 31, 24.6%), gynecologic (n=31, 214.6%), other GI (n=20, 15.9%), and breast (n= 16, 12.7%) primary sites (Figure 3). Most actionable findings were found in the second review (n= 106, 83.1% of those with multiple reviews). Most common actionable finding was PD L1 status (n=24, 19.1%) followed by tumor mutational burden (TMB), (n=23, 18.3%). Other common actionable findings included FOLR 1 (n=15, 11.9%), FGFR (n= 11, 8.7%), PIK3CA (n=11, 8.7%), HER2/ERBB2 (n=9, 7.1%), BRCA2 (n=6, 4.76%) (Figure 3).
Figure 3: Heatmap of actionable findings in NGS testing for patients reviewed multiple times with recommended therapy associations.
Heat map of actionable findings in NGS testing for those reviewed multiple times. Each row represents a patient. Gender, primary site, stage, number of reviews, and corresponding recommended treatment for the actionable finding are designated.
Survival
Univariate analysis was used to compare patients with one review to patients with multiple reviews. The analysis showed that primary site and stage are significantly associated with overall survival. In multivariate analysis, after adjusting for primary site and stage, patients with multiple reviews had a 30% lower risk of death compared to those with one review (HR 0.7, 95% CI 0.55–0.89, p = 0.003) (Figure 2a). Multiple reviews remained associated with better overall survival when primary site, age, presence of actionable finding on NGS reports, and stage were controlled for in the model (HR 0.7, CI 0.55–0.89, p = 0.004).
Figure 2: Overall Survival.
Figure 2A: Overall survival between those reviewed once and those reviewed multiple times at UK MTB
Kaplan Meier curve showing overall survival of those reviewed once at UK MTB compared to those reviewed multiple times at UK MTB.
Figure 2B: Overall survival between those reviewed once, twice, and three or more times at UK MTB
Kaplan Meier curve showing overall survival of those reviewed once at UK MTB compared to those reviewed two and three or more times at UK MTB.
Comparing patients with one review to patients with two reviews and patients with one review to those with three or more reviews, after adjusting for primary site and stage, patients with two reviews had 25% lower risk of experience death than the patients with only one review (HR 0.75, 95% CI 0.58–0.97, p = 0.03); patients with three or more reviews had 56% lower risk of experiencing death than patients with only one review (HR 0.44, 95% CI 0.22–0.89, p = 0.02) (Figure 2b). With the addition of age and presence of actionable findings to the multivariate analysis model, two reviews remained significantly associated with overall survival compared to one review (HR 0.75, 95% CI 0.58–0.97, p = 0.03). Three or more reviews also remained significantly associated with overall survival compared to one review (HR 0.45, 95% CI 0.22–0.91, p = 0.02).
Discussion:
As patients receive treatment, tumors evolve and acquire new somatic mutations that can lead to resistance to certain therapies.11 Sequential NGS is often performed at time of recurrence, but few studies have demonstrated clinical benefit. One study published in prostate cancer showed sequential NGS testing identified actionable mutations in 11% (n=16) of 144 patients, with 13% (n=5) patients receiving a targeted or immunotherapy based on that result.19 While the current study found a slight difference in actionable findings between those reviewed once and those with multiple MTB reviews at initial review, approximately 50% of patients had actionable findings in both cohorts. The majority of patients reviewed multiple times still had actionable findings at their 2nd and 3rd or more review. Despite findings that those reviewed once had a slightly higher proportion of elevated TMB and PD-L1 positivity at initial review compared to multiple reviews, those reviewed multiple times still received clinically relevant therapy recommendations. Of those who had multiple MTB reviews and had available treatment history, over 50% received recommended treatment between both their first and second and second and third reviews, and average time of both recommended immunotherapy and targeted therapy was over six months in the multiple review cohort. This adds to the literature that multiple MTB review and sequential NGS testing is clinically reasonable at recurrence across multiple tumor types to identify actionable findings that can guide valuable treatment.
Molecular tumor board reviews can help guide treatment in a heavily pre-treated population and sequential NGS testing with multiple reviews at MTB shows a benefit to overall survival. Multiple molecular tumor board reviews were more likely to occur in younger patients, those with recurrent disease, and in certain primary sites such as breast, gynecologic, colorectal, and other gastrointestinal cancers. In addition, patients who underwent sequential NGS testing and who were reviewed multiple times at molecular tumor board had an improved overall survival compared to those reviewed once, even after controlling for primary site, age, stage, and presence of actionable findings on NGS results. While this survival finding is possibly due to tumor sensitivity to various therapies that incur a survival advantage and allow for sequential NGS testing and multiple reviews, this advantage highlights the clinical benefit of sequential NGS testing and the role that MTB can play in interpreting those results and recommending therapies that can lengthen overall survival.
Multiple factors can explain these findings. Younger patients may be healthier at baseline than older patients and may be willing to undergo multiple additional lines of treatment, leading to multiple MTB reviews. Those with recurrent disease may be heavily pre-treated with multiple chemotherapies, immunotherapies and targeted agents, some of which can change tumor mutational profile and warrant change in therapy that is molecularly directed.10 Certain primary sites have sequential NGS testing at time of recurrence recommended in clinical guidelines, including colorectal, lung, head and neck, breast and prostate cancers.12–16 Breast and colorectal primaries were more common in the multiple review cohort, while lung and head and neck were more common in the single review cohort. This may indicate an area for improvement in lung and head and neck care to further advocate for sequential NGS at time of recurrence and use of MTBs to help guide care. As patients recur on various therapies, clinicians may turn to MTB multiple times to help guide treatment or recommend clinical trial options.
Patients reviewed multiple times had an improved overall survival compared to those reviewed just once at MTB, and this continued to be significant on multivariate analysis. Multiple prior studies have indicated that MTB can improve PFS and OS in multiple cancer types, including NSCLC, breast and gynecologic cancers.2, 6, 7, 20, 21 This study is the first to show a survival benefit to sequential NGS testing with multiple MTB reviews, and is one of the few studies to examine the utility of multiple MTB reviews. While this advantage is possibly due to tumor therapy sensitivity, having multidisciplinary teams to help guide treatment at time of recurrence and after heavy pre-treatment with multiple agents can be helpful to clinicians and may yield a survival advantage for patients.
Limitations of this study include that it was performed at a single institution with a majority non-Hispanic White population, and thus the results may not be generalizable to all populations. Referral patterns and use of MTB may also be biased based on institutional patterns. In addition, a potential survival bias exists for those undergoing multiple reviews as they had to live long enough to undergo repetitive testing, possibly due to tumor therapy sensitivity; nevertheless, the survival benefit of multiple MTB reviews persisted after controlling for multiple factors associated with survival. It should also be noted that this study was not a randomized control trial, and while this study demonstrates a strong association in the findings, a randomized control trial would be necessary to confirm these findings. Finally, as complete case analysis was utilized, some observations were excluded due to missing covariate data. This may have reduced estimate precision and introduced potential bias if the missingness was related to the outcome or key exposures. Therefore, results should be interpreted with caution. Strengths of this study include large sample size, inclusion of prospectively collected data, and diverse primary site inclusion.
In conclusion, this study is the first to show an overall survival advantage to sequential next-generation sequencing with multiple molecular tumor board reviews and indicates that sequential NGS testing yields actionable findings that lead to meaningful time on recommended targeted treatment. While these findings may be attributable to therapy sensitivity and a randomized control trial would be necessary to confirm the above findings, this study highlights the clinical advantage of sequential next-generation sequencing and the value of molecular tumor boards to institutions and patient care.
Supplementary Material
-
Key objective:
Is there clinical benefit to multiple molecular tumor board reviews of sequential next-generation sequencing?
-
Knowledge generated:
Patients reviewed once had modestly higher proportion of actionable findings compared to those reviewed multiple times at initial review, and approximately half of patients at their 2nd and 3rd or more reviews had actionable findings. Patients with multiple MTB reviews had a 30% lower risk of death compared to those reviewed once, even after controlling for primary site, age, presence of actionable NGS findings, and stage, though this may reflect tumor therapy sensitivity.
-
Relevance:
Sequential next-generation sequencing with multiple reviews by molecular tumor board can yield clinically meaningful actionable findings that can drive treatment options and a possible overall survival advantage.
Acknowledgements/Support:
National Cancer Institute at the National Institutes of Health, Division of Cancer Epidemiology and Genetics, grant number P30CA177558, B. Mark Evers and was supported by the Biostatistics and Bioinformatics Shared Resource, the Biospecimen Procurement and Translational Pathology Shared Resources, and the Cancer Research Informatics Shared Resource.
Footnotes
Conflicts of Interest: None
Notification of Publication: An abstract for this manuscript was included as an online-only abstract for the 2025 ASCO Annual Meeting.
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