Highlights in Pathology: Gynaecologic Oncology (April 2020)
Dr. Tomer Feigenberg, Gynaecologic Oncologist, Trillium Health Partners
The following highlights have been chosen to represent different aspects of Medical Genetics and Genomics encompassing infectious disease characterization, cancer genetics, prenatal genetics and data privacy.
1. Mismatch repair deficiency as a predictive marker for response to adjuvant radiotherapy in endometrial cancer
Gynecol Oncol. 2019 Jul;154(1):124-130
The mismatch repair (MMR) system promotes DNA repair by means of an excision mechanism during DNA replication.
MMR deficiency is a common feature of endometrial cancer and is present in approximately 20 to 40% of cases. MMR deficiency may be inherited or acquired.
Microsatellite instability status was identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas (TCGA).
MMR status may impact outcomes and response to chemotherapy for patients diagnosed with endometrial cancer, however it’s impact on adjuvant radiotherapy is not well identified.
To investigate the predictive value of MMR status for response to adjuvant radiotherapy in a group of patients with stage IB/II, grade 3 endometroid endometrial cancer.
Retrospective multicenter study included patients with histo-pathologically confirmed stage IB or II grade 3 EEC treated between 2005 and 2012.
All patients underwent hysterectomy. If lymphadenectomy was performed, it had to be negative.
Only patients who received no adjuvant therapy or adjuvant radiotherapy were included. Patients who received chemotherapy were excluded.
Mismatch repair deficiency (MMR-D) was defined as total loss of nuclear staining of one or more MMR proteins, in presence of an intact internal control.
A total of 128 patients were included for analysis.
Median follow-up time was 36 months.
Radiotherapy was given in 82 patients (64.1%), whereas 46 patients (35.9%) did not receive any adjuvant treatment.
27 patients (21.1%) received vaginal brachytherapy, whereas 55 patients (43.0%) received external beam radiotherapy (with or without brachytherapy).
MMR- deficiency was identified in 57 patients (44.5%).
Patients with MMR-deficient EECs presented with FIGO stage II more often than patients with MMR-proficient EECs.
The recurrence rates were 28.1% and 40.0% for MMR-deficient and MMR-proficient cases, respectively.
Radiotherapy was associated with an improved OS in patients with MMR-deficient EECs (HR0.36, 95%- CI 0.14–0.92, p = 0.032), however no benefit was seen in patients with MMR-proficient EECs.
In both patients with MMR-deficient EECs and MMR-proficient EECs, improvement in PFS was seen from adjuvant radiotherapy. In multivariable analysis, adjusting for FIGO-stage, LVSI and age, adjuvant radiotherapy was associated with improved OS (p = 0.021) for patients with MMR-deficient, but not for patients with MMR proficient tumors.
No difference in out- comes was seen between patients treated with vaginal brachytherapy compared to EBRT.
Conclusions and clinical implications
Adjuvant radiotherapy may improve survival in patients with MMR-deficient high grade endometroid endometrial cancer.
As our province moved to reflexive MMR testing for all patients diagnosed with endometrial cancer, timely MMR status testing could become a valuable predictive marker for selection of appropriate patients who may benefit from adjuvant radiotherapy.
2. Histopathological characterization of ProMisE molecular groups of endometrial cancer
Gynecol Oncol. 2020 Jan 10. pii: S0090-8258(20)30008-1
While Endometrial cancer is the most prevalent cancer among gynecologic cancers in high income countries, poorly reproducible histopathologic assessment of specimens remains a problem.
As a result, some patients may be over or undertreated based on traditional risk factors.
The Proactive Molecular Risk Classifier for endometrial Cancer (ProMisE) is emerging as a novel molecular classifier based on the Cancer Genome Atlas (TCGA) Research Network findings on endometrial cancer subgroups.
The ProMisE classifier identified four molecular group of endometrial cancer with different prognosis:
- POLE-mutated (POLEmt), characterized by good prognosis, very high mutational rate and mutations in the exonuclease domain of Polymerase-ε (POLE); such group may be identified only by sequencing
- mismatch repair-deficient (MMR-d), characterized by intermediate prognosis, high mutational rate and microsatellite-instability; such group may be detected by immunohistochemistry for mismatch repair proteins
- p53-abnormal (p53-abn), characterized by poor prognosis, TP53 muta- tions, low mutational rate, and high somatic copy number alterations rate; such group may be diagnosed by abnormal immunohistochemical expression of p53
- p53-wild-type (p53-wt), characterized by good-to-intermediate prognosis, low mutational and somatic copy number alterations rates; such group is the less defined one, showing no specific molecular signature.
A systematic review and meta-analysis aiming to provide a histopathological characterization of ProMisE groups of endometrial cancer, in terms of histological grade, histotype, lymphovascular space invasion (LVSI), myometrial invasion, lymph node involvement, and European Society for Medical Oncology (ESMO) risk category.
912 patients from three studies with no overlapping cases were included in the meta-analysis.
Out of these 912 patients:
- 232 (25.4%) were MMR-d
- 84 (9.2%) were POLE-mt
- 430 (47.1%) were p53-wt
- 166 (18.2%) were p53-abn.
Overall, 729 carcinomas (79.9%) were pure endometrioid and 138 (15.1%) were pure serous. The remaining cases were mixed histotypes.
MMR-d group: MMR-d endometrial cancers were endometrioid in most cases (85.8%), and showed G3, LVSI, and deep myometrial invasion in almost half cases. Based on traditional risk factors, this group has a high percentage of patients that would be classified as high risk, and about 30% of patients that would be classified as low risk.
As such, in view of the know intermediate risk of MMR-d tumor, significant percentage of these patients may be over or under treated.
POLE-mt group: This group shows a high prevalence of G3 (39.6%) and high prevalence of parameters of aggressiveness (LVSI-positive = 32.7%, deep myometrial invasion = 27.3%), however, the POLE-mt group was the only group that showed null prevalence of lymph node involvement (0%).
These findings strengthen the proposal of considering POLE-mt patients as stage I endometrial cancer at low risk regardless of other traditional risk factors. To date, many of these patients are overtreated.
P53-wt group: The p53-wt group showed the most favorable clinicopathological profile among the 4 groups. Most p53-wt ECs are low-grade endometrioid carcinomas with low rates of Parameters of aggressiveness (LVSI = 13.8%, deep myometrial invasion = 27.4%, lymph node involvement = 4.3%).
In general, the management of patients in this group might be little affected by a molecular-based reclassification and most patients are considered low to intermediate risk category.
P53-abn group: This group shows the most unfavorable histopathological profile among the four ProMisE groups. Unfavorable histopathological characteristics was the highest in this group (G3 = 90%, deep myometrial invasion = 48.9%, LVSI = 48.8%, lymph node involvement = 23.7%). The prevalence of endometrioid histotype was the lowest (27%) in this group. The majority of patients in this group are classified as high-risk category (84.7%), while only a minority was classified at low- risk (7.2%).
Therefore, similarly to the p53-wt group, the p53- abn group may be little affected by a molecular-based revision of the risk assessment system, however such a revision would affect about 15% of EC patients who would be reclassified as high risk regardless of favorable traditional histological characteristics.
Conclusions and clinical implications
The histopathological characterization of endometrial cancer is currently challenging, with low reproducibility and inter-observer variations.
Comparing traditional known risk factors such as depth of myometrial invasion, LVI and lymph-nodes involvement to new ProMisE groups of endometrial cancer shows that a significant percentage of patients are currently under- or overtreated across the several ProMisE groups, specifically in the POLE-mt and MMR-d groups.
Future clinical trials are urgently needed to assess if this new classification can lead to better patient care and tailored surgical and adjuvant strategies.
3. Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making
Gyn Onc. 2020 Mar;156(3):517-522
Genetic risk evaluation is an important component of care for women with epithelial ovarian, peritoneal or fallopian tube cancer.
Germline genetic testing identifies BRCA1 or BRCA2 mutations in 15% of unselected ovarian carcinomas (OC) and mutations in other cancer susceptibility genes are present in an additional 4% of cases.
Both germline and somatic genetic aberrations are associated with the development and treatment of OC, emphasizing that genetic assessment is integral to modern management.
Recently, the SOLO-1 trial reported outcomes for the PARPi (Olaparib) as maintenance monotherapy following response to first-line platinum-based chemotherapy in patients with BRCA-mutated OC. SOLO-1 showed an impressive benefit for PARPi maintenance, with a 70% lower risk of disease progression or death compared to placebo and an improvement in progression-free survival of 36 months.
Presence of a germline or somatic BRCA mutation was a requirement for study entry, but only 0.5% BRCA mutations in SOLO-1 were somatic.
Two main strategies have been proposed to integrate germline and somatic testing;
- ASCO guideline emphasizes starting with germline testing of all OC patients for susceptibility genes and proceeding with somatic testing if a BRCA1 or BRCA2 pathogenic or likely pathogenic variant are not found in the germline.
- Others have suggested that somatic testing be completed first for HGSOC with a reflex to germline testing for abnormal somatic results.
To report the experience with clinical testing of paired tumor and germline DNA for OC mutations.
Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue. All medical records of OC cases tested from 7/2017 to 7/2018 (43 patients). They calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist including 69 cancer susceptibility genes.
- 51% of patients had pathogenic germline mutations and/or actionable somatic mutations
- 14% had germline mutation
- 35% had somatic mutation
Most germline mutations were found in BRCA1, BRCA2, and PMS2 genes and were all associated with somatic loss of heterozygosity.
One patient with the PMS2 mutation had high microsatellite instability, and 2 patients had CHEK2 mutation.
Of the 16 somatic mutations, only 56.3% were in BRCA1 or BRCA2 genes, while 31.3% occurred in other HR genes and two (12.5%) were in non-HR genes (one in PMS2 and one in BRAF.)
The total rate of pathogenic germline and actionable somatic mutations in high grade serous carcinomas (HGSC) was 60% versus 31% in the 13 non-serous cases (these patients are generally not tested in Ontario).
Stratified by disease status at the time of testing, results impacted clinical decision-making in nine of 34 (26%) newly diagnosed patients, and three of six (50%) recurrent cases.
Conclusions and clinical implications
Simultaneous germline and somatic targeted sequencing was a high-yield strategy for all patients with OC.
These data highlight the importance of performing germline genetic testing in patients with OC regardless of histologic subtype, as currently recommended by NCCN.
Pathogenic germline mutations and/or potentially actionable somatic mutations was identified in one-half of cases. Identifying these mutations early during the cancer journey has significant clinical implications mainly related to maintenance strategies as early as the completion of first line chemotherapy.
Currently, in Ontario only patients diagnosed with HGSOC are funded for both germline and somatic testing.
The current study identified a significant proportion of germline and somatic mutations in actionable genes other than BRCA1 and BRCA 2. While some centres use wide gene panels for testing, these approaches have not yet become a standard of care in many centres.
4. Incidence of pelvic lymph node metastasis using modern FIGO staging and sentinel lymph node mapping with ultrastaging in surgically staged patients with endometrioid and serous endometrial carcinoma
Gynecol Oncol.2020; April 1
Staging of endometrial cancer is prognostic and aids in adjuvant treatment planning.
Sentinel lymph node (SLN) mapping for staging of apparent uterine-confined endometrial cancer is now considered an acceptable method for surgical staging by the National Comprehensive Cancer Network (NCCN).
The FIRES trial, published in 2016, was the first prospective cohort study to examine the use of SLN mapping and ultra-staging in early-stage endometrial cancer. While the study included all histologic subtypes across multiple institutions, few high-grade cases were included.
To assess the incidence of occult nodal metastasis in patients who underwent primary surgical staging for apparent early endometrioid or serous endometrial cancer with bilateral SLN mapping and ultra-staging. Occult ovarian metastasis rates were also reported.
Of 1044 patients, 959 had endometrioid and 85 serous carcinomas.
There were no positive SLNs among 510 patients with non-invasive FIGO grade 1/2 endometrioid carcinoma and < 1% ITCs.
- Grade 1: 4.5% with inner-half and 10% with outer-half myometrial invasion had positive SLNs.
- Grade 2: rates were 4% and 20%, respectively.
- Grade 3: 5% with non-invasive, 3% with inner-half, and 24% with outer-half myometrial invasion had positive SLNs.
Overall, all patients with endometroid histology and inner half invasion have comparable risk of lymph node involvement.
ITC incidence increased with depth of myometrial invasion—25% of deeply invasive grade 1/2 and 18% of deeply invasive grade 3 tumors.
Four (10%) of 41 patients with non-invasive serous endometrial carcinoma had ITCs or positive SLNs.
Conclusions and clinical implications
This is the largest cohort of sentinel lymph node mapping in endometrial cancer, with a relative large cohort of patients diagnosed with serous histology.
The results may help guide clinical decisions making in endometrial cancer in an era when many centres adapt sentinel lymph node mapping as standard of care for all patients diagnosed with endometrial cancer.
Patients diagnosed with non-invasive low-grade disease are at very low risk of nodal involvement and ITC, as such, ultra-staging protocols can potentially be spared for those patients.
Patients with serous histology and non-invasive tumors have a 5% risk of ITC which may alter clinical management of these patients, as such, the current study supports the use of SLN in high grade disease.