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Prognosis of isolated tumor cells and use of molecular classification in early stage endometrioid endometrial cancer
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  1. Eric Rios-Doria1,
  2. Nadeem R Abu-Rustum1,2,
  3. Kaled M Alektiar3,
  4. Vicky Makker4,5,
  5. Ying L Liu4,5,
  6. Dmitriy Zamarin4,5,
  7. Claire F Friedman4,5,
  8. Carol Aghajanian4,5,
  9. Lora H Ellenson6,
  10. Sarah Chiang6,
  11. Britta Weigelt6,
  12. Jennifer J Mueller1,2 and
  13. Mario M Leitao1,2
    1. 1 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    2. 2 Department of OB/GYN, Weill Cornell Medical College, New York, New York, USA
    3. 3 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    4. 4 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    5. 5 Department of Medicine, Weill Cornell Medical College, New York, New York, USA
    6. 6 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    1. Correspondence to Dr Mario M Leitao, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA; leitaom{at}mskcc.org

    Abstract

    Objective We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease.

    Methods Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January 1, 2007 to December 31, 2019. All SLNs underwent ultrastaging according to the institutional protocol. Patients with cytokeratin positive cells, micrometastases, and macrometastases were excluded. Clinical, pathology, and molecular subtype data were reviewed.

    Results Overall, 1214 patients with early stage endometrioid endometrial cancer met the inclusion criteria, of whom 1089 (90%) had node negative disease and 125 (10%) had isolated tumor cells. Compared with node negative disease, the presence of isolated tumor cells had a greater association with deep myometrial invasion, lymphovascular space invasion, receipt of adjuvant therapy, and adjuvant chemotherapy with or without radiation (p<0.01). There was no significant difference in survival rates between patients with isolated tumor cells and node negative disease (3 year progression free survival rate 94% vs 91%, respectively, p=0.21; 3 year overall survival rate 98% vs 96%, respectively, p=0.45). Progression free survival did not significantly differ among patients with isolated tumor cells who received no adjuvant therapy or chemotherapy with or without radiation (p=0.31). There was no difference in the distribution of molecular subtypes between patients with isolated tumor cells (n=28) and node negative disease (n=194; p=0.26). Three year overall survival rates differed significantly when stratifying the entire cohort by molecular subtype (p=0.04).

    Conclusions Patients with isolated tumor cells demonstrated less favorable uterine pathologic features and received more adjuvant treatment with similar survival compared with patients with nodenegative disease. Among the available data, molecular classification did not have a significant association with the presence of isolated tumor cells, although copy number-high status was a poor prognostic indicator in early stage endometrioid endometrial cancer.

    • Endometrial Neoplasms
    • Uterine Cancer

    Data availability statement

    Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

    https://doi.org/10.1136/ijgc-2024-005522

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • Patients with macrometastases and micrometastases benefit from adjuvant chemotherapy, but appropriate management of isolated tumor cells is controversial.

      WHAT THIS STUDY ADDS

      • In our cohort of patients with early stage endometrioid endometrial cancer and either isolated tumor cells or node negative disease, patients with isolated tumor cells demonstrated less favorable uterine pathologic features and received more adjuvant treatment with similar survival compared with those with node negative disease.

      • Molecular classification did not have a significant association with the presence of isolated tumor cells, although copy number-high status was a poor prognostic indicator in early stage endometrial cancer.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • Uterine factors, not the presence of isolated tumor cells alone, should dictate adjuvant treatment recommendations.

      • Future studies should investigate the use of endometrial molecular subtyping for further stratification of isolated tumor cells.

      Introduction

      Endometrial cancer is the most common gynecologic malignancy in the US, with an estimated 66 200 cases diagnosed in 2023.1 Surgical staging includes lymph node assessment, which has implications for staging and clinical decision making for adjuvant treatment.2 Compared with pelvic and para-aortic lymphadenectomy, sentinel lymph node (SLN) dissection has higher accuracy with less morbidity.3 Ultrastaging has enhanced the detection of nodal metastases within SLNs,4 5 which has led to increased identification of small volume nodal metastasis, particularly isolated tumor cells.6–8

      Patients with macrometastases and micrometastases benefit from adjuvant chemotherapy4 9 10; however, appropriate management of isolated tumor cells is controversial. In 2019, the Society of Gynecologic Oncology published a survey reporting that 21% of respondents acknowledged that patients with isolated tumor cells should be treated as patients with node positive disease.11 While SLN mapping was introduced to avoid the postoperative morbidity associated with lymphadenectomy (lymphocele, lymphoedema, and lymphorrhagia), it can lead to treatment escalation.3 12–16 The therapeutic implications of a non-standardized approach for patients with isolated tumor cells has enabled the search for a deeper understanding of isolated tumor cells in endometrial cancer.

      We evaluated the prognosis of patients with early stage endometrioid endometrial cancer with isolated tumor cells compared with node negative disease. We also assessed uterine factors and evaluated molecular classification in patients with isolated tumor cell positive and node negative disease.

      Methods

      Patients with stage IA, IB, or II endometrioid endometrial cancer who underwent surgical staging with SLN ultrastaging at our institution from January 1, 2007 to December 31, 2019 were identified. Pathology reports were reviewed, and stage at diagnosis was based on the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging criteria. SLN dissection and ultrastaging were performed according to our institutional protocol.5 Isolated tumor cells were defined as measuring <0.2 mm or <200 cells when tumor cells were present as individual cells and/or clusters occupying lymph node sinuses. We excluded patients with cytokeratin only positivity within SLN ultrastaging and the presence of either micrometastases or macrometastases. Patients with node negative disease must have received SLN dissection with ultrastaging and no presence of isolated tumor cells, micrometastases, or macrometastases. All SLNs were reviewed by gynecologic pathologists at our institution, and data were abstracted from synoptic pathology reports.

      Tumors were classified as DNA polymerase ε (POLE), microsatellite instability-high, copy number-high/TP53abnormal, or copy number-low/no specific molecular profile molecular subtypes using results from clinical tumor normal next generation sequencing (MSK-IMPACT) and immunohistochemistry using an institutional algorithm.17–20 Patients were classified as high–intermediate risk by Gynecologic Oncology Group (GOG)-249 criteria.21 Adjuvant treatments included none, chemotherapy with or without radiation therapy, and radiation therapy alone. All treatment was administered at our institution.

      Categorical variables were compared with the χ2 or Fisher's exact test. Continuous variables were compared with the Mann–Whitney test. Progression free survival was defined from date of surgery to date of recurrence or last gynecologic assessment. Overall survival was defined from date of surgery to date of death or last known contact. Kaplan–Meier analysis and log rank tests were used for survival estimates. Differences in node status and adjuvant treatment were compared. In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the editorial team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.

      Results

      We identified 1214 patients with early stage endometrioid endometrial cancer who met the inclusion criteria. SLN ultrastaging detected isolated tumor cells in 125 patients (10%), and 1089 (90%) had node negative disease (Table 1). Median age at diagnosis of endometrial cancer for patients with isolated tumor cells was 63 years (range 26–87) and 61 years (4–92) for patients with node negative disease (p=0.07). Median body mass index was similar for patients with isolated tumor cells (median 30.9 kg/m2, range 15.1–61.7) and those with node negative disease (30.0 kg/m2, 16.7–67.6; p=0.26). When comparing patients with isolated tumor cells versus node negative disease, 43% (53 of 125) versus 14% (152 of 1089) had stage IB/II disease (p<0.01), 41% (51 of 125) versus 13% (137 of 1089) had tumors with >50% myoinvasion (p<0.01), and 77% (96 of 125) versus 23% (252 of 1089) had tumors with lymphovascular space invasion (p<0.01). There was no significant association with other pathological characteristics, including FIGO grade and cytology status.

      Median number of SLNs removed was three for both groups (range 1–14 for the isolated tumor cell group and 1–18 for the node negative group; p<0.01). SLNs only were removed in 776 patients (64%; 683 with node negative disease and 93 with isolated tumor cells). For patients with additional non-SLNs removed (n=438), the median number of non-SLNs removed for patients with isolated tumor cells was 3 (range 1–35), and 4 (1–48) for those with node negative disease (p=0.99).

      View this table:
      Table 1

      Clinical, pathologic, and molecular characteristics of patients with sentinel lymph node removal and ultrastaging with no findings (node negative) or isolated tumor cells

      Patients with isolated tumor cells were more likely to have primary uterine tumors meeting high–intermediate risk criteria (63% vs 23%, p<0.01) and receive adjuvant treatment (87% vs 40%, p<0.01). For patients with isolated tumor cells, the most common treatment modality was chemotherapy with or without radiation (62%), while no treatment (59%) or radiation treatment alone (35%) were most common among patients with node negative disease (Table 1). In both the high–intermediate and low–intermediate risk criteria groupings, patients with isolated tumor cells were more likely to receive adjuvant therapy with chemotherapy with or without radiation (low–intermediate risk: 50% vs 3%, p<0.01; high–intermediate risk: 70% vs 19%, p<0.01; online supplemental Table 1).

      Supplemental material

      Median follow-up time was 36.5 months (range 0.4–167). Three year progression free survival rate was 94% (standard error (SE)±2.4%) for patients with isolated tumor cells and 91% (±1.0%) for patients with node negative disease (p=0.21; Figure 1A). Three year overall survival rate for patients with isolated tumor cells was 98% (SE±1.4%) and 96% (±0.7%) for patients with node negative disease (p=0.45; Figure 1B). Within the isolated tumor cell cohort, 3 year progression free survival rate was 100% for patients without adjuvant treatment, 95.3% (SE±2.7%) for those who received chemotherapy with or without radiation, and 88.3% (±6.4%) for those treated with radiation alone (p=0.31; online supplemental Figure 1).

      Figure 1
      Figure 1

      Survival outcomes for patients with isolated tumor cells compared with node negative sentinel lymph node status. (A) Progression free survival. (B) Overall survival.

      Molecular subtype was available for 222 patients, 28 (13%) with isolated tumor cells and 194 (87%) with node negative disease. Distribution by molecular subtype was not significantly different between the groups; among 28 patients with isolated tumor cells, 1 (4%) had POLE, 11 (39%) microsatellite instability-high, 2 (7%) copy number-high/TP53abnormal, and 14 (50%) copy number-low/no specific molecular profile molecular subtypes. Among 194 patients with node negative disease, 36 (19%) had POLE, 67 (34%) microsatellite instability-high, 13 (7%) copy number-high/TP53abnormal, and 78 (40%) copy number-low/no specific molecular profile subtypes (p=0.26).

      Survival outcomes were assessed for 199 (90%) of 222 patients who underwent clinical tumor normal sequencing of the primary tumor before recurrence. Compared with the other subtypes, copy number-high/TP53abnormal portended the worst survival outcomes, with a 3 year progression free survival rate of 77% (SE±11.7%; p=0.18; Figure 2A) and a 3 year overall survival rate of 74% (±16.1%; p=0.04; Figure 2B). Further statistical analysis was not performed because only 13 patients with node negative disease and two with isolated tumor cells had the copy number-high/TP53abnormal subtype.

      Figure 2
      Figure 2

      Survival outcomes for whole patient cohort by the Cancer Genome Atlas (TCGA) molecular subtype. (A) Progression free survival. (B) Overall survival. POLE, polymerase epsilon; MSI-H, microsatellite instability high, CN-H/TP53abn, copy number-high/TP53abnormal; CN-L/NSMP, copy number-low/no specific molecular profile.

      The overall recurrence rate was 6% (7 of 125) for patients with isolated tumor cells and 8% (89 of 1089) for those with node negative disease. Presence of locoregional or distant recurrence did not differ by treatment modality among the whole cohort (Table 2). Of the seven patients with isolated tumor cells who had a recurrence, five were diagnosed at a distant site, including the para-aortic chain, liver, or lung (Table 3); external beam radiation with or without chemotherapy was initially prescribed to treat four of these patients. Three patients met the high–intermediate risk criteria, two of whom had the microsatellite instability-high molecular subtype. One patient with resultant distant site recurrence (liver) did not meet the high–intermediate risk criteria or receive any adjuvant treatment and had the POLE molecular subtype. The remaining two patients with locoregional recurrence met the high–intermediate risk criteria, were treated with intravaginal radiation therapy, and had recurrence at the vaginal apex. Among the 89 patients with node negative disease who recurred, 52 (58%) had locoregional recurrence, 37 (42%) had distant metastasis, and 41 (46%) met the high–intermediate risk criteria.

      View this table:
      Table 2

      Breakdown of recurrences (n=96) by location and receipt of adjuvant therapy

      View this table:
      Table 3

      Clinical, pathologic, and molecular subtype characteristics for patients with isolated tumor cells who had a recurrence

      Among patients with the copy number-high/TP53abnormal molecular subtype, recurrences only occurred in the node negative group, with 5 (38%) of 13 patients having recurrence (median follow-up 28.0 months).

      Discussion

      Summary of Main Results

      Our study provides an update on the prognosis of isolated tumor cells in endometrioid endometrial carcinoma over a 13 year period, during which time the prevalence of isolated tumor cells increased and the SLN mapping algorithm became well established. Among all patients with stage I or II endometrioid endometrial carcinoma who were treated at our institution from 2007 to 2019, 10% had isolated tumor cells. The presence of isolated tumor cells was significantly associated with myoinvasion, lymphovascular space invasion, and high–intermediate risk criteria. We found a non-significant difference in progression free survival between patients with node negative disease versus isolated tumor cells, which is consistent with our previous report (Figure 1A).4 We also assessed isolated tumor cells using modern molecular classification, and our findings highlight the need for future studies.

      Results in the Context of Published Literature

      Detection of lymph node metastases in patients without extrauterine disease has increased following the introduction of the SLN mapping algorithm.22 This algorithm has been beneficial to patient care, demonstrating less surgical morbidity compared with full lymphadenectomy and a low false negative rate.3 Increased detection of low volume disease and isolated tumor cells has introduced uncertainty in management guidelines. The current treatment paradigm for patients with isolated tumor cells within SLNs is highly individualized and considers uterine factors. The distribution of adjuvant treatment differed within our cohort: patients with isolated tumor cells were more likely to receive chemotherapy with or without radiation compared with those with node negative disease, who were more likely to receive no adjuvant treatment. This finding correlates with the increased proportion of patients in the isolated tumor cell group meeting GOG-249 high–intermediate risk criteria.

      Our previous report on low volume disease included isolated tumor cells, micrometastases, and serous and clear cell histologies.4 Patients with isolated tumor cells were more likely to be treated with chemotherapy with or without radiation than those in our current analysis (87% vs 62%, respectively). The previous study retrospectively reviewed patients from 2005 to 2013, during which time the presence of nodal metastases included isolated tumor cells, micrometastases, or macrometastases. Thus patients with isolated tumor cells without micrometastases or macrometastases were upstaged to stage IIIC rather than the pN0(i+) designation established by the American Joint Committee on Cancer and adopted by the National Comprehensive Cancer Network.2 23

      Synoptic pathology reports in this study differentiated between cytokeratin positive cells and cells meeting our institutional criteria for isolated tumor cells, which requires both hematoxylin–eosin and cytokeratin positive cell staining. Our gynecologic disease management team currently does not consider cytokeratin positive cells alone as isolated tumor cells, as they are usually only found in rare, isolated cytokeratin cells and not on hematoxylin–eosin staining.5 Assigning cytokeratin positive cells alone as isolated tumor cells is controversial within the breast cancer literature, although they are thought to represent iatrogenic displacement of epithelial cells.24–27 Our previous study assessed outcomes and found no significant difference in 3 year recurrence free survival rates between node negative disease (93%) and isolated tumor cells (94%) in patients with endometrioid endometrial carcinoma (p<0.01), but only 23 patients with isolated tumor cells were studied.

      Backes et al explored a multi-institutional cohort of 175 patients with isolated tumor cells, concluding that the presence of isolated tumor cells should not be used as a predictive biomarker when deciding whether to prescribe adjuvant therapy.28 Over half of the study’s patient population, however, had cytokeratin positive cells without the use of hematoxylin–eosin staining when defining isolated tumor cells. Our study excluded cytokeratin positive cells identified in SLN ultrastaging. Similar to Backes et al, we did not find a statistically significant impact of adjuvant treatment on outcomes in patients with isolated tumor cells, although only 13% of patients with isolated tumor cells in our cohort received no adjuvant therapy. While there does not appear to be a survival advantage with adjuvant therapy, further research is needed before establishing a standardized recommendation.

      A recent multi-institutional study by Cucinella et al evaluated isolated tumor cells in patients with stage IA endometrioid endometrial cancer, with either FIGO grade 1 or 2 disease, and without receipt of adjuvant therapy.29 Among 42 patients with isolated tumor cells and 452 with node negative disease, a survival advantage was observed for progression free survival but not for overall survival, suggesting that the presence of isolated tumor cells alone is a negative prognosticator. Ultrastaging was not performed in all patients, however, and inclusion of cytokeratin only positivity was not mentioned. Our study included 629 patients who met Cucinella et al’s criteria, including 15 patients with isolated tumor cells and 614 with node negative disease. No significant differences in progression free or overall survival were observed in our cohort, even when controlling for lymphovascular space invasion; however, we were limited by the small number of patients for this analysis (data not shown). This study raises important questions for the prognosis of patients who have low risk disease with isolated tumor cells, and a prospective study for this unique group is being planned.

      We also assessed four molecular subtypes proposed by the Cancer Genome Atlas, and found no significant association between POLE, microsatellite instability-high, copy number-high/TP53abnormal, or copy number-low/no specific molecular profile subtypes and isolated tumor cells or node negative disease; however, our analysis was limited by the number of tumors with known molecular subtypes. In our study, the copy number-high/TP53abnormal subtype had poor survival outcomes, which is consistent with the aggressive nature of this molecular subtype20 30; thus, its prognostic value in isolated tumor cells should be addressed in future studies.

      Recurrence is often a concern in patients with isolated tumor cells. Previous studies have shown varied recurrence rates, ranging from 0% to 9%,4 6 31 32 which has caused debate regarding the management of isolated tumor cells. Within our cohort, seven patients with isolated tumor cells had a recurrence, two of whom had isolated disease within the para-aortic lymph nodes; both had stage I disease, were treated with chemotherapy and external beam radiation, and had similar uterine factors. One patient was characterized as high–intermediate risk with microsatellite instability-high status, while the other was not high–intermediate risk and had an unknown molecular subtype (Table 3). Molecular subtyping may aid in the development of a new combined uterine factor risk categorization and is being actively investigated in prospective clinical trials.33 34 While few patients with sequencing results met our inclusion criteria for molecular subtype assignment (≥20% tumor purity, presence of somatic mutations, unambiguous subtype classification), we observed all subtypes in the isolated tumor cell cohort.35 Recurrences were found in patients with POLE and microsatellite instability-high subtypes; however, additional studies are needed to determine the prognostic value of molecular subtypes.

      Our results did not demonstrate a strong indication for treatment of isolated tumor cells. This should be interpreted with caution, as data on the treatment of isolated tumor cells are rare and generally driven by uterine factors. Overall, 63% of patients in our cohort met the high–intermediate risk criteria, and 62% of patients with isolated tumor cells received chemotherapy. The current definition of isolated tumor cells used in gynecologic pathology is derived from the breast cancer literature and was arbitrarily chosen by the American Joint Committee on Cancer.36 37 Given the varied responses and presentations among patients with isolated tumor cells, the prognostic value of these definitions in gynecologic oncology is debated. Future research should focus on SLN ultrastaging slides and in-depth characterizations of the histologic pattern of isolated tumor cells.

      Strengths and Weaknesses

      Our study was strengthened by the number of patients who underwent the ultrastaging protocol. While there was overlap in the study period with our previous report, the increasing frequency of ultrastaging and advancements in our electronic medical record allowed for greater screening and capturing of patients with isolated tumor cells. We also recognize the limitations inherent in retrospective studies. Follow-up for patients with early stage endometrioid endometrial cancer can be up to 5 years. Our patients transition to a survivorship clinic for continued surveillance or may choose to follow-up with a local provider; thus, patients may have sought care at another institution for recurrence. Lastly, our molecular subtyping analysis was limited by the available molecular data available (222 of 1214 patients, 18%).

      Implications for Practice and Future Research

      Our findings indicate that uterine factors, not the presence of isolated tumor cells alone, should dictate adjuvant treatment recommendations. Additional research is needed to examine whether there is a survival advantage with adjuvant therapy, to determine the prognostic value of molecular subtypes in endometrioid endometrial cancer, and to investigate the use of molecular subtyping for further stratification of isolated tumor cells.

      Conclusion

      To our knowledge, this is the only series to explore molecular subtyping in patients with endometrioid endometrial cancer and isolated tumor cells or node negative disease. Isolated tumor cells were identified in 10% of tumors that underwent SLN ultrastaging over a 13 year period. The presence of isolated tumor cells was associated with less favorable uterine pathologic features and more adjuvant therapy, including chemotherapy; however, patients with isolated tumor cells had similar survival outcomes to those with node negative disease. The survival impact of postoperative treatment is difficult to measure, as only 13% of patients with isolated tumor cells were treated with surgery alone and an individualized approach for adjuvant therapy is favored. Despite limited data within our cohort, molecular classification did not have a significant association with the presence of isolated tumor cells, although the copy number-high/TP53abnormal subtype was a poor prognostic indicator, even in early stage disease.

      Data availability statement

      Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This retrospective study was approved by the institutional review board at Memorial Sloan Kettering Cancer Center. Participants gave informed consent to participate in the study before taking part.

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      Footnotes

      • X @RiosDoriaMD, @leitaomd

      • Contributors ER-D: conceptualization, data curation, formal analysis, methodology, and writing–review and editing. NRA-R, KA, VM, YLL, DZ, CFF, CAA, LE, SC, and BW : writing–review and editing. JM: conceptualization, data curation, formal analysis, methodology, writing–original draft, and writing–review and editing. ML: conceptualization, formal analysis, methodology, and writing–review and editing, guarantor.

      • Funding Research reported in this publication was supported in part by a National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA008748). BW is supported in part by Cycle for Survival, NIH/NCI (P50 CA247749), and Breast Cancer Research Foundation grants.

      • Competing interests BW reports research support by Repare Therapeutics, outside of the current work. CAA reports clinical trial funding paid to the institution from AstraZeneca; funding paid to the institution from BMS and SELLAS Life Sciences Group; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). DZ reports institutional grants from Genentech, AstraZeneca, BMS, SELLAS Life Sciences Group, and Plexxikon; personal fees from Genentech, AstraZeneca, Xencor, Memgen, Synthekine, Celldex, and Hookipa; and stock options from Immunos, Accurius, Mana Therapeutics, and Calidi Biotherapeutics, outside of the submitted work. DZ is also an inventor on a patent related to the use of oncolytic Newcastle disease virus for cancer therapy. YLL reports research funding from AstraZeneca, GSK, and Repare Therapeutics. NRA-R reports research funding paid to the institution from GRAIL. ML reports research funding paid to the institution from KCI/Acelity, ad-hoc speaker for Intuitive Surgical, and advisory board participation for JnJ/Ethicon and Takeda. VM reports advisory board participation (unpaid) for Eisai, Merck, Clovis, Faeth, Duality, Morphyes, Karyopharm, Novartis, Lilly, and Immunocore. CFF reports participation in the scientific advisory boards for Merck (LYNK-002) and Genentech (MyPathway) without compensation, consulting for Seagen and Bristol Myers Squibb, and institutional research funds from Genentech/Roche, Bristol Myers Squibb, Merck, AstraZeneca, and Daiichi. SC serves as a consultant for AstraZeneca.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.