A prospective study of Annual Whole-Body MRI (WBMRI) as Part of a Multimodality Screening Program for Individuals with Li-Fraumeni Syndrome (LFS)

Abstract

PURPOSE:

Individuals with Li-Fraumeni syndrome (LFS) are at risk for developing cancer in multiple organs and therefore require a multimodal screening program. We assessed the performance of annual whole-body non-contrast MRI (WBMRI) in early cancer detection for individuals with LFS.

METHODS:

Individuals with a germline pathogenic or likely pathogenic variant in the TP53 gene (defined as LFS) and without cancer diagnosed or treated in the preceding 6 months were eligible to undergo annual non-contrast WBMRI. Clinical findings on WBMRI, follow-up studies, biopsies, and cancer incidence were prospectively assessed.

RESULTS:

162 participants (pts) with LFS (127 adult, 35 pediatric) underwent 477 WBMRIs; 119 (73%) underwent 3 or more. Median age at enrollment was 37 years; 75% of pts were female. Classic or Chompret diagnostic criteria for LFS were met for 68.5% of pts. Follow-up studies for findings on WBMRI were pursued for 55.6% of pts. Biopsies were performed in 18% of pts; 39.5% of 38 biopsies confirmed a cancer diagnosis. The rate of follow-up interventions decreased with consecutive WBMRIs. During the study period, of 37 cancers diagnosed in 33 pts, 15 (40.5%) were diagnosed by WBMRI; 86% (13/15) were asymptomatic, localized cancers treated with curative intent. The 22 cancers not diagnosed on WBMRI included five sarcomas, one each of adrenocortical, lung, thyroid and renal cell carcinoma and 13 cancers WBMRI would not be expected to detect.

CONCLUSION:

Annual WBMRI contributes substantially to the detection of asymptomatic localized cancers among individuals with LFS and is best utilized in conjunction with a multimodality approach endorsed by LFS guidelines. Our study highlights the need for further research to enhance early detection and interception of cancer in LFS.

BACKGROUND

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome characterized by an increased risk of developing diverse adult and pediatric malignancies ^1–5. LFS is caused by inherited or de-novo germline or mosaic pathogenic/ likely pathogenic (P/LP) variants in the TP53 gene ^6–8. Because of the high risk of developing malignancies in multiple organs, a multimodal screening program for individuals with LFS is recommended by several guidelines ^9–13. Such screening programs include comprehensive physical exams and focused breast, dermatological and neurological exams, upper endoscopies and colonoscopies, brain MRIs, breast MRIs, mammograms, and in children, abdominal ultrasounds.

Whole-body MRI (WBMRI) is also recommended for individuals with LFS as part of the multimodal screening approach known as the “Toronto protocol” ¹⁴, and has been incorporated into AACR and NCCN consensus guidelines ^12,15. Data assessing the utility of WBMRI for surveillance in patients with LFS are evolving ^16–22. High sensitivity and negative predictive values of WBMRI were initially reported ²³ but false negatives (missed cancers) have also been described ^19,24. A meta-analysis of 578 individuals with LFS (including 60 from our institution) estimated that the overall detection rate of new localized malignant neoplasms by a single baseline scan was 7%; the false-positive rate was 42.5% ^23,25. However, mature data reporting outcomes of longitudinal WBMRI screening over several years are limited. NCCN guidelines also highlight that WBMRI utility has not been sufficiently evaluated among those with a germline TP53 P/LP variant without a classic family history of LFS, and neither WBMRI nor insurance coverage for WBMRI are widely available

We conducted a prospective study incorporating WBMRI into a multimodality cancer surveillance program for pediatric and adult individuals with LFS. We report herein the feasibility, diagnostic accuracy and outcomes of patients diagnosed with cancer while undergoing this longitudinal surveillance program.

METHODS

We conducted a prospective cohort study to test the utility of annual non-contrast WBMRI for screening in individuals with LFS. Non-contrast MRI of the brain and body was performed as previously described (technical information available in the Supplement ^18,25). Individuals were included if they were carriers or obligate carriers of a P/LP TP53 variant per ClinVar classification ²⁶, or as reported by one or more established commercial laboratories. Reasons for patient exclusion from the analytic cohort due to ineligibility are outlined in Figure 1. Variants that were classified in ClinVar as benign, likely benign, or VUS (n=8) as of 12/01/2022, were reviewed by an expert panel. Individuals carrying these benign or VUS variants were excluded (n=6 variants in 20 subjects); as the panel concluded that there was sufficient evidence to classify the other 2 variants as P/LP, those carriers were retained. Individuals whose initial TP53 variant was subsequently proven to be somatic rather than germline were excluded (n=3).

Figure 1. CONSORT diagram of individuals with Li-Fraumeni Syndrome who were screened with WBMRI.

Reasons for exclusion of study participants from the analysis cohort are listed for each study site.

DFCI: Dana-Farber Cancer Institute

BCH: Boston Children’s Hospital

MSKCC: Memorial Sloan Kettering Cancer Center

Individuals with LFS underwent WBMRI annually at the Dana-Farber Cancer Institute (DFCI), Boston Children’s Hospital (BCH) or Memorial Sloan Kettering Cancer Center (MSKCC) if they continued to meet eligibility criteria. The study was able to provide up to 4 annual scans but allowed collection of data for additional scans if performed. Individuals received multimodal surveillance per NCCN and/or AACR guidelines at DFCI, BCH, MSKCC, or locally. Participants who underwent at least one WBMRI during the study period were included in this analysis.

Individuals with a prior history of cancer or cancer diagnosed during the study were eligible if they were in remission and at least 6 months from the completion of curative-intent treatment. Subjects with a history of breast cancer were permitted to undergo WBMRI while receiving anti-hormonal and/or HER2-directed therapy. Individuals with active cancer or metastatic disease (except in the case of Stage 0 chronic lymphocytic leukemia or nonmelanoma skin cancer) were excluded. Patients with a metal heart valve, surgical clips, a pacemaker or any other indwelling metal device that might interfere with MRI and females who were pregnant or nursing were excluded. Pediatric TP53 carriers with a contraindication to sedation or general anesthesia required for WBMRI were also excluded.

The outcomes of longitudinal WBMRI screening, including required follow up studies, biopsies and pathologically confirmed cancer diagnoses were prospectively documented. Data regarding interval cancer diagnoses between WBMRIs or up to 18 months after conclusion of on-protocol WBMRIs were also collected. Cancer diagnoses were reviewed by the study team, including a retrospective radiologist review of the preceding WBMRI and additional follow-up imaging studies to adjudicate the modality leading to cancer diagnoses. The primary objective was to describe the detection of asymptomatic cancer by WBMRI, and to estimate the proportion of patients whose cancer was first diagnosed by WBMRI rather than another modality. The primary endpoint is the modality that first identified the cancer diagnosis, WBMRI or another modality. Secondary objectives included describing the results of serial scanning and the requirement for dedicated imaging or biopsy in follow-up to WBMRI. The most recent date of follow-up was reported for each patient, and a data snapshot for this analysis was taken on December 15^th, 2022. The study was approved by the institutional IRB and all participants or legal guardians signed informed consent (NCT02950987); pediatric participants age 10 years or older provided assent.

Statistical methods.

Statistical analyses were descriptive and not inferential including calculation of medians (range) and frequencies (percentage). Pediatric patients were defined as ≤18 years of age at study enrollment. For most analyses, the experimental unit was an individual patient; however, when this was a cancer diagnosis was the experimental unit, this is explicitly specified in table titles/headers. The proportion of diagnoses that were detected by WBMRI was calculated overall, by the number of WBMRI scans performed, and for each cancer site: (number of diagnoses first diagnosed by WBMRI) divided by (number of patients screened with WBMRI). Analyses were performed using R version 4.0.2.

RESULTS

Participant and study characteristics

The study population included 162 adult and pediatric individuals with P/LP variants in TP53 who underwent a total of 477 WBMRIs (Table 1) as part of a multimodal surveillance program for LFS. The first and last dates of WBMRI scans were 3/29/2012 and 9/8/2022, respectively. The overall median age at enrollment was 37 years; 35 (21.6%) pediatric participants had a median age of 8.2 years (Table 1). Seventy-five percent of participants were assigned female sex at birth. A personal history of cancer was reported in 73/127 (57%) adults versus 6/35 (17%) pediatric participants. A family history of cancer was reported in 95.6% of participants. Classic LFS Diagnostic Criteria ²⁷ were met for 20% (26/127) of adult and 37% (13/35) of pediatric participants. Chompret 2015 Criteria for LFS ⁴ were met by 46% (58/127) of adult and 40% (14/35) of pediatric participants (Table 1).

Table 1.

Characteristics of patients with Li-Fraumeni syndrome screened with WBMRI (n=162)

Characteristic	Overall n= 162	Adult n=127 (78.4%)	Pediatric n=35 (21.6%)
	median (range)
Age at enrollment (years)	36.9 (1.2, 82.3)	40.5 (19.6, 82.3)	8.2 (1.2, 16.3)
	n (%)
Sex (Female)	122 (75.3)	102 (80.3)	20 (57.1)
Previous history of cancer
Yes	79 (49.1)	73 (57.5)	6 (17.6)
No	82 (50.9)	54 (42.5)	28 (82.4)
Unknown	1	0	1
Status at last follow up
Deceased	9 (5.6)	7 (5.5)	2 (5.7)
Alive	153 (94.4)	120 (94.5)	33 (94.3)
Family history of cancer
Yes	154 (95.6)	121 (96.0)	33 (94.0)
No	7 (4.4)	5 (4.0)	2 (6.0)
Unknown	1	1	0
LFS diagnosis criteria met by participant
Classic	39 (24.1)	26 (20.5)	13 (37.1)
Chompret	72 (44.4)	58 (45.7)	14 (40.0)
Neither	51 (31.5)	43 (33.9)	8 (22.9)
Number of WBMRIs*
1	19 (11.7)	15 (11.8)	4 (11.4)
2	24 (14.8)	24 (18.9)	0 (0)
3	86 (53.1)	79 (62.2)	7 (20.0)
4	21 (12.9)	8 (6.3)	13 (37.1)
5**	7 (4.3)	1 (0.8)	6 (17.1)
6	2 (1.2)	0	2 (5.7)
7	3 (1.9)	0	3 (8.6)
Underwent anesthesia for WBMRI		0
Yes	21 (13)	0	21 (60.0)
No	141 (87)	127 (100)	14 (40.0)
Number of dedicated follow-up studies
0	72 (44.4)	49 (38.6)	23 (65.7)
1 or more	90 (55.6)	78 (61.4)	12 (34.3)
1	47 (29.0)	41 (32.3)	6 (17.1)
2	27 (16.7)	23 (18.1)	4 (11.4)
3	10 (6.2)	9 (7.1)	1 (2.9)
4	6 (3.7)	5 (3.9)	1 (2.9)
Number of biopsies performed for WBMRI findings
0	133 (82.1)	101 (79.5)	32 (91.4)
1 or more	29 (17.9)	26 (20.5)	3 (8.6)
1	21 (13.0)	18 (14.2)	3 (8.6)
2	7 (4.3)	7 (5.5)	0
3	1 (0.6)	1 (0.8)	0

^*Total number of WBMRIs = 477

^**One patient had a WBMRI scan performed outside of DFCI, BCH or MSKCC

The median number of WBMRI scans completed per individual was three, with 119 (73%) individuals undergoing at least three sequential WBMRI scans (Table 2). Over half of participants (n=90, 56%) required at least one follow-up study after WBMRI; 29 (18%) required a biopsy for WBMRI findings (Tables 1,2). No significant adverse events were reported following WBMRI or during follow up imaging studies or biopsies. Among 29 participants who underwent 38 biopsies (Table 1), 15 cancers were diagnosed by WBMRI, including one cancer diagnosed by a WBMRI scan performed outside of DFCI or MSKCC (Table 2).

Table 2.

Sequence of WBMRI scans and timing of other follow-up studies, biopsies, and cancer diagnoses (n=162)

WB-MRI scan number	Adults/Pediatric patients	Number of patients evaluated	Number of patients undergoing follow-up studies n (%)	Number of follow-up studies for WB-MRI findings	Number of patients undergoing biopsies n (%)	Number of biopsies for WB-MRI findings	Number of patients diagnosed with cancer by WB-MRI n (%)	Number of cancer diagnoses based on WB-MRI	Number of patients diagnosed with interval diagnoses n (%)	Number of interval cancer diagnoses not detected on WB-MRI
1	Overall	162	60 (37.0)	80	20 (12.3)	21	6 (3.7)	7	8 (4.9)	8
	Adult	127	56 (44.1)	74	19 (15.0)	20	6 (4.7)	7	6 (4.7)	6
	Pediatric	35	4 (11.4)	6	1 (2.9)	1	0 (0)	0	2 (5.7)	2
2	Overall	143	38 (26.6)	42	12 (8.4)	13	6 (4.2)	6	7 (4.9)	9
	Adult	112	33 (29.5)	37	12 (10.7)	13	6 (5.4)	5	7 (6.3)	9
	Pediatric	31	5 (16.1)	5	0 (0)	0	0 (0)	1	0 (0)	0
3	Overall	119	21 (17.6)	24	3 (2.5)	3	0 (0)	0	3 (2.5)	3
	Adult	88	19 (21.6)	22	2 (2.3)	2	0 (0)	0	3 (3.4)	3
	Pediatric	31	2 (6.4)	2	1 (3.2)	1	0 (0)	0	0 (0)	0
4	Overall	33	5 (15.2)	6	1 (3.0)	1	1 (3.0)	1	2 (6.1)	2
	Adult	9	1 (11.1)	1	0 (0)	0	0 (0)	0	0 (0)	0
	Pediatric	24	4 (16.7)	5	1 (4.2)	1	1 (4.2)	1	2 (8.3)	2
5	Overall	11	1 (9.1)	1	0 (0)	0	1 (9.1)**	1	0 (0)	0
	Adult	1	0 (0)	0	0 (0)	0	0 (0)	0	0 (0)	0
	Pediatric	10	1 (10.0)	1	0 (0)	0	1 (10.0)	1	0 (0)	0
6	Overall	5	1 (20.0)	1	0 (0)	0	0 (0)	0	0 (0)	0
	Adult	0	0 (0)	0	0 (0)	0	0 (0)	0	0 (0)	0
	Pediatric	5	1 (20.0)	1	0 (0)	0	0 (0)	0	0 (0)	0
7	Overall	3	1 (33.3)	1	0 (0)	0	0 (0)	0	0 (0)	0
	Adult	0	0 (0)	0	0 (0)	0	0 (0)	0	0 (0)	0
	Pediatric	3	1 (33.3)	1	0 (0)	0	0 (0)	0	0 (0)	0

^*Interval detected cancers are defined as those diagnosed by an approach other than WB-MRI

^**Cancer diagnosed by a WBMRI scan performed outside of DFCI, BCH or MSKCC

Cancer diagnoses during the study follow up period

In total, there were 37 new cancer diagnoses among 33 (20%) individuals enrolled (Table 3, Supplementary Table 1). The most common primary tumors detected were bone and soft tissue sarcomas (n=8), lung (n=4), thyroid (n=4) and breast cancers (n=3). The most frequent metastatic tumor diagnosed on study was breast cancer (n=3). Of the cancer diagnoses on study, 15 (40.5%) were detected using WBMRI and 22 (59%) were identified as detailed below and in Table 3 and Figure 2. The 22 cancers not diagnosed based on WBMRI included five sarcomas, and one each adrenocortical carcinoma, lung cancer, thyroid cancer and renal cell carcinoma. Other primary neoplasms not detected on WBMRI were in organs/system not well visualized on WBMRI and not expected to be detected on WBMRI- three breast cancers, and endoluminal tumors of the uterus, bladder, and buccal mucosa, as well as hematologic malignancies (Table 3, Supplementary Table 1).

Table 3.

Characteristics of cancers diagnosed during the study follow up period (n=37 diagnoses in n=33 patients)

Patient ID	Sex	Diagnostic modality leading to cancer diagnosis	WBMRI on which or after which cancer was diagnosed (time between WBMRI and diagnosis, when applicable)	Age at diagnosis (years)	Tumor location and stage*	Primary / recurrent	Tumor histology
D119	Female	WB-MRI	1st	58	Thyroid (L)	primary	Papillary thyroid microcarcinoma
D5	Female	WB-MRI	1st	40	Thyroid (L)	primary	Follicular thyroid carcinoma
D126	Female	WB-MRI	1st	61	Lung (L)	primary	Lung adenocarcinoma
D15	Male	WB-MRI	1st	54	Lung (L)	primary	Lung adenocarcinoma
D79	Female	WB-MRI	1st	39	Ischioanal fossa (pelvis) (L)	primary	Leiomyosarcoma
D30	Female	WB-MRI	1st	40	Clivus (skull base) (L)	primary	Chordoma
D79	Female	WB-MRI	1st	39	Parietal lobe (CNS) (L)	primary	Low-grade glioma
K06	Female	WB-MRI	1st	32	L5 bone (M)	Recurrent	Metastatic breast adeoncarcinoma
D2	Male	WB-MRI	2nd	43	Thyroid (L)	primary	Papillary thyroid carcinoma
D97	Female	WB-MRI	2nd	45	Lung (M)	recurrent	Invasive ductal carcinoma of the breast
D98	Female	WB-MRI	2nd	35	Lung (L)	primary	Lung adenocarcinoma
D84	Female	WB-MRI	2nd	66	Pelvis (L)	primary	Leiomyosarcoma
D12	Female	WB-MRI	2nd	40	Pancreas (L)	primary	Pancreatic ductal adenocarcinoma
B21	Male	WB-MRI	4th	13	Pelvis (iliac bone) (L)	primary	right iliac chondrosarcoma
B7	Male	WBMRI (off protocol, performed clinically at home institute)	4th	12	Pelvis (L)	primary	Osteosarcoma
D39	Female	Symptomatic	1st (74 days)	30	Breast (L)	primary	Malignant phyllodes tumor
B42	Female	Symptomatic	1st (299 days)	16	Tibia (L)	primary	intermediate grade osteosarcoma
D7	Female	Symptomatic	1st (188 days)	62	Endometrium (uterus) (L)	primary	Serous adenocarcinoma
D11	Female	Symptomatic	1st (326 days)	30	Liver (M)	recurrent	Invasive ductal carcinoma of the breast
D33	Female	Symptomatic	1st (249 days)	38	Parietal lobe (CNS) (M)	recurrent	Lung adenocarcinoma
D111	Female	Symptomatic	2nd (131 days)	51	Breast (L)	recurrent	Invasive ductal carcinoma of the breast
D19	Male	Symptomatic	2nd (223 days)	64	Thigh (cutaneous) (L)	primary	Primary cutaneous anaplastic large cell T-cell lymphoma
D19	Male	Symptomatic	2nd (264 days)	64	Thigh (cutaneous) (L)	primary	Atypical intradermal smooth muscle neoplasm vs leiomyosarcoma
D60	Female	Symptomatic	2nd (21 days)	44	Gluteal region (cutaneous) (L)	primary	Leiomyosarcoma
D128	Male	Symptomatic	2nd (45 days)	27	Buccal mucosa (L)	primary	Squamous cell carcinoma
D116	Female	Symptomatic	2nd (194 days)	31	Bladder (L)	primary	Papillary urothelial carcinoma
D128	Male	Symptomatic	2nd (121 days)	27	Thyroid (L)	primary	Papillary thyroid carcinoma
D10	Male	Surveillance for previous cancer	1st (241 days)	75	Pelvis (M)	recurrent	Prostate adenocarcinoma
D79	Female	Surveillance for previous cancer	2nd (266 days)	39	Adrenal gland (L)	primary	Adrenocortical carcinoma
D46	Female	Routine Screening	1st (369 days)	38	Breast (L)	primary	Invasive ductal carcinoma of the breast
D53	Female	Routine Screening	2nd (87 days)	50	Chest wall / breast (L)	primary	Spindle cell sarcoma
B30	Male	Routine screening	4th (314 days)	11	Kidney (L)	primary	Renal cell carcinoma
D93	Female	Other: follow-up imaging for benign WBMRI finding (blood clot)	3rd (104 days)	26	Lung (L)	primary	Lung adenocarcinoma
D77	Female	Symptomatic	3rd (266 days)	27	Humeral region soft tissue (L)	primary	Atypical lipomatous tumor vs well-differentiated liposarcoma
B1	Female	Lab work	4th	18	Bone Marrow (NA)	primary	Leukemia
K05	Male	Lab work	1st	13	Bone Marrow (NA)	primary	t-AML/MDS
D52	Female	Lab work	3rd (90 days)	54	Peripheral blood and lymph nodes (M)	primary	Chronic lymphocytic leukemia

^*L: Localized cancer. M: metastatic cancer

Figure 2.

Number and percentage of patients who had follow-up studies (blue bars), biopsies (yellow bars), cancers diagnosed based on WBMRI (grey bars), or cancers diagnosed by an approach other than WBMRI (burgundy bars), by WBMRI sequence number. Sample sizes (i.e., the number of patients used as the denominator) are shown for each WBMRI sequence # (n=7), with the number of individual patients indicated at the top of each bar.

* Interval detected cancers are defined as those diagnosed by an approach other than WBMRI, in the interval of time between WBMRIs, or up to 18 months after the participant’s last WBMRI

The median age of cancer diagnosis was 39 (IQR 26–50); 26 of 37 (70%) cancer diagnoses were among females, who comprised 75% of the study cohort. More than one third of cancers (n=17, 46%) were diagnosed in the 39 participants (24%) meeting Classic LFS Criteria (Supplementary Table 2). Forty percent (15 of 37) of cancers were diagnosed among individuals meeting Chompret Criteria (72 of 162 [44%] met Chompret Criteria).

Longitudinal WBMRI surveillance results

The number and percentage of participants requiring follow up studies, biopsies, and those participants diagnosed with cancer by sequential WBMRI scan are presented in Table 2 and Figure 2. Among 162 participants undergoing their first WBMRI, 60 (37.0%) required one or more follow-up studies and 20 (12.3%) underwent one or more biopsies. The seven diagnoses made by the first WBMRI were in 6/162 (3.7%) participants and all were localized: two lung cancers, two thyroid cancers, two CNS tumors, and a pelvic leiomyosarcoma (Table 3).

The second round of WBMRI identified 4 localized cancers and 2 metastatic malignancies in 6/143 (4.2%) participants. Among these was a localized pancreatic cancer that was not seen on initial WBMRI and a leiomyosarcoma that was thought to represent a benign finding on initial WBMRI but demonstrated concerning interval growth on the second WBMRI. Findings from subsequent WBMRIs are presented in the tables and figures detailed above. Participants did not all complete 4 WBMRI because of a cancer diagnosis, transfer of care, or loss to follow-up. Among those who underwent 4 or more WBMRI (n=33), two had cancer detected on WBMRI.

Cancers not detected on WBMRI

In the follow up period of up to 18 months after their first WBMRI (and before their second WBMRI, when applicable), 8/162 (4.9%) patients were diagnosed with cancer (Table 2) based on symptoms or other screening modalities, including two localized breast cancers, and one each: osteosarcoma of the tibia, serous adenocarcinoma of the uterus, and acute myeloid leukemia (AML). Three metastatic recurrences of previous cancers were also diagnosed (Table 3).

Following the second WBMRI, 7/143 (4.9%) patients were diagnosed with nine cancers based on other modalities, including three sarcomas (spindle cell sarcoma of the chest wall, leiomyosarcoma in the gluteal region, and an atypical intradermal smooth muscle neoplasm of the thigh) and an adrenocortical carcinoma (Table 3).

There were three interval cancer diagnoses in three patients made after their third WBMRI. These included a lung cancer arising in a nodule initially thought to be benign but demonstrating significant interval growth (Table 3). The two cancer diagnoses after a 4^th WBMRI were in pediatric patients - a leukemia and a renal cell carcinoma at 18 and 11 years of age, respectively.

Cancer characteristics and outcomes

Of the 15 cancers first diagnosed based on WBMRI findings, 13 (86%) cancers in 12 patients were localized primary malignancies and two were breast cancer recurrences (Table 3). The 22/37 (59%) cancers that were not detected on WBMRI were diagnosed based on symptoms (13/22, 59%), other components of routine LFS screening (3/22, 14%), surveillance for a previous malignancy (2/22, 9.1%), abnormal blood work (3/22, 13.6%), and follow up imaging for a non-malignant finding on WBMRI (1/22) (Table 3). Of the 22 cancers not detected by WBMRI, 14 (64%) cancers in 12 patients were localized cancers that were treated with curative intent.

At the time of data cutoff, 9 study participants (2 pediatric), had died, including one individual with metastatic pancreatic cancer (initially found as localized disease on WBMRI), two with metastatic breast cancer, and one who was diagnosed with metastatic lung cancer during the study period and subsequently developed gastric cancer and myelodysplastic syndrome (MDS). Two patients succumbed to AML - one diagnosed during the study period and one participant who completed 3 WBMRIs and was diagnosed with AML more than 3 years after her last WBMRI. One patient died of metastatic osteosarcoma and two patients died of unknown causes. Ten of 12 patients who were diagnosed with localized cancers on WBMRI and were treated with curative intent were alive at their last follow-up. One patient has experienced a metastatic recurrence of leiomyosarcoma. All 12 patients diagnosed with localized cancer that was not detected on WBMRI were alive at the time of last follow-up.

DISCUSSION

To our knowledge, this is one of the largest studies reporting on sequential WBMRI, in combination with a comprehensive screening protocol, for the early detection of cancer among individuals with LFS, and includes 477 WBMRI scans performed on 127 adult and 35 pediatric individuals. Over 80% of WBMRI-detected cancers in our study were diagnosed at a localized stage and treated with curative intent, highlighting WBMRI’s utility for early cancer detection. The 22/37 (59.5%) cancer diagnoses made in the interval between scans and by additional surveillance modalities corroborate existing data to suggest that WBMRI does not substitute for a comprehensive, multimodal approach to surveillance, including a history and physical exam, dedicated breast MRI, endoscopies and other surveillance modalities.

Multiple groups have now reported their experience with an initial WBMRI for individuals with LFS ^{14,16–19,23,25,28–30}; the diagnostic yield of WBMRI in these studies and cohort characteristics were recently summarized ³¹, but detailed data regarding longitudinal screening are limited^17,29. Kagami et al recently described the outcomes of longitudinal WBMRI for 118 individuals, of whom approximately 90% met either Classic or Chompret criteria for LFS; data regarding interval diagnoses were not available for this dataset ³¹. Most studies report that a large proportion of patients require follow-up studies ( “false-positives”). Our study confirmed a high rate of initial follow-up studies (37% of participants), which decreased with subsequent scans as noted by Kagami et al³¹. Additionally, the cancer detection rate on first WBMRI and among pediatric participants in our study is lower than previous studies ^14,25.

Villani et al described the outcomes of the first multimodality screening approach including WBMRI, in which WBMRI and brain MRI detected approximately 50% of cancers, suggesting that WBMRI (using the Toronto protocol) may be insufficient as a sole screening modality ¹⁴. In our study, WBMRI detected sarcomas primarily in the pelvic region, whereas extremity, chest wall and superficial sarcomas were not found, even on retrospective review. Additionally, after data cut-off, a study participant was reported to have been diagnosed with glioblastoma, although we were not able to confirm this with a pathology report. There is currently variable practice as it relates to brain imaging with dedicated MRI and little consensus regarding screening recommendations for sarcoma sites not well imaged by WBMRI. Additionally, there is no consensus regarding screening for additional cancers for which effective screening methods exist, such as lung and pancreatic cancer^32,33. Lung cancer was notably common in our study, suggesting that lung nodules among individuals with LFS may require closer follow-up with a lower threshold for tissue sampling, consistent with previous reports ^29,34–37. There is intense interest in evaluating other promising technologies, including multiple serial cell-free DNA approaches by the Toronto group, the Early Detection In Syndromic Cancers (EDISYN) consortium and others ³⁸.

In our study, sequential WBMRI was important not only for detection of new lesions, but also for follow up of previous findings, including those initially considered benign but which showed evidence of progression on a subsequent examination. Biopsies were performed in fewer than 20% of participants (only 8.6% of pediatric participants) and led to a cancer diagnosis in almost 40% of these cases. Detailed evaluation of surveillance imaging findings is critical to try to improve the accuracy of WBMRI; for example, pediatric WBMRIs are formally reviewed at a multidisciplinary conference at BCH.

There is a paucity of data regarding the utility of WBMRI in individuals representing the range of LFS phenotypic subtypes ³⁹, particularly individuals with a germline TP53 P/LP variant with a less penetrant phenotype ³⁹. In our study, WBMRI detected cancer in individuals across the LFS spectrum, including three (5.9%) of 51 individuals not meeting Classic or Chompret criteria, who comprised almost a third of our study cohort. Further research is needed to identify subgroups of individuals with LFS who could benefit from intensification of or reduction in screening, and to determine the optimal frequency of WBMRI.^29,34–37. Taken together, these data demonstrate the safety, feasibility, and utility of annual WBMRI and support guidelines recommending WBMRI in individuals with LFS. However, WBMRI is not uniformly available without an official diagnostic code in the United States. Lack of uniform insurance coverage for WBMRI may result in worse outcomes for patients from rural, underserved, and lower socioeconomic communities. Our study did not directly address cost of care, but we encountered no difficulty with insurance coverage for diagnostic tests and procedures following WBMRI.

Our study has several limitations. All participants were enrolled at academic medical centers in the northeastern United States. Because WBMRI costs were covered, we are unable to assess factors that may result from reduced access to healthcare. In addition, the intervals between WBMRIs in our study were not uniformly 1-year (Supplementary Figure 1). Lastly, we excluded individuals with cancer diagnosis/treatment in the prior 6 months but in clinical practice it may be reasonable to perform WBMRI for such individuals given the risk of synchronous malignancies.

Despite these limitations, our findings support the continued use of annual WBMRI for individuals with LFS notwithstanding the difficulties with insurance coverage and at the same time, highlight the need for further research to advance early detection and prevention of cancer in individuals with LFS.

Supplementary Material

PV Data Supplement_3

Supplementary Figure 1a. A histogram of time interval between WB-MRI scans (n=458 WB-MRI scans in 143 patients with two or more WB-MRIs)

PV Data Supplement_4

Supplementary Figure 1b. Box and Whisker plot of time interval between WBMRI scans, by number of WBMRIs [n=143 patients with two or more WBMRIs]. [2 WBMRIs (1 interval) n=48; 3 WBMRIs (2 intervals) n=258; 4 WBMRIs (3 intervals) n=84; 5 WBMRIs (4 intervals) n=35; 6 WBMRIs (5 intervals) n=12; 7 WBMRIs (6 intervals) n=21]

PV Data Supplement_5

Supplementary Figure 1c. Box and Whisker plot of time interval between WBMRI scans (n=458 WBMRI scans in 143 patients with two or more WBMRIs, n=6 WBMRI scans with intervals greater than 730 days and diagnosed with cancer were highlighted in red)

Context Summary.

Key objective:

What is the contribution of annual whole-body MRI (WBMRI) to the detection of asymptomatic, curable cancers among individuals with Li-Fraumeni Syndrome (LFS) undergoing a longitudinal multimodality screening program?

Knowledge generated:

In this prospective study including adult and pediatric participants across the LFS phenotypic spectrum, 13 of 37 (35.1%) cancers diagnosed during the study period were asymptomatic, localized cancers that were identified on WBMRI and treated with curative intent. Cancers diagnosed by methods other than WBMRI highlight the importance of a comprehensive multimodality screening program for individuals with LFS, and the need for further research to advance early detection and prevention of cancer in individuals with LFS.

Relevance:

These data highlight that WBMRI should be made widely available to individuals with LFS and covered by payers.