Published Ahead of Print on February 22, 2018 as 10.1634/theoncologist.2017-0526.

Precision Medicine Clinic: Molecular Tumor Board

Complete Remission Following Pembrolizumab in a Woman with

Mismatch Repair-Deficient Endometrial Cancer and a Germline
BRCA1 Mutation
DON S. DIZON ,a,b DORA DIAS-SANTAGATA,d AMY BREGAR,c,e LAURA SULLIVAN,d JENNIFER FILIPI,d ELIZABETH DITAVI,c LUCY MILLER,d
LEIF ELLISEN,d,e MICHAEL BIRRER,f MARCELA DELCARMENc,d,e
a
Lifespan Cancer Institute and Rhode Island Hospital, Providence, Rhode Island, USA; bAlpert Medical School of Brown University,
Providence, Rhode Island, USA; cDivision of Gynecologic Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA;
d
Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; eHarvard Medical School, Boston, Massachusetts, USA;
f
University of Alabama Cancer Center, Birmingham, Alabama, USA
Disclosures of potential conflicts of interest may be found at the end of this article.

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ABSTRACT
Endometrial cancer is the most common gynecologic malig-
nancy in the U.S. and, although the majority of cases present at
an early stage and can be treated with curative intent, those
who present with advanced disease, or develop metastatic or
recurrent disease, have a poorer prognosis. A subset of endo-
metrial cancers exhibit mismatch repair (MMR) deficiency. It is
now recognized that MMR-deficient cancers are particularly
susceptible to programmed cell death protein 1 (PD-1)/
programmed death-ligand 1 (PD-L1) inhibitors, and in a land-
mark judgement in 2017, the U.S. Food and Drug Administration
granted accelerated approval to pembrolizumab for these
tumors, the first tumor-agnostic approval of a drug. How-
ever, less is known about the sensitivity to PD-1 blockade
among patients with known mutations in double-strand
break DNA repair pathways involving homologous recombi-
nation, such as those in BRCA1 or BRCA2. Here we report a
case of a patient with an aggressive somatic MMR-deficient
endometrial cancer and a germline BRCA1 who experienced
a rapid complete remission to pembrolizumab. The
Oncologist 2018;23:1–4

KEY POINTS
• Endometrial cancers, and in particular endometrioid carcinomas, should undergo immunohistochemical testing for
mismatch repair proteins.
• Uterine cancers with documented mismatch repair deficiency are candidates for treatment with programmed cell death
protein 1 inhibition.
• Genomic testing of recurrent, advanced, or metastatic tumors may be useful to determine whether patients are candidates
for precision therapies.

PATIENT STORY
A 42-year-old woman with a history of stage IVB Hodgkin’s
lymphoma, originally diagnosed in 2010, was treated with bev-
acizumab plus standard chemotherapy (doxorubicin, bleomy-
cin, vincristine, and dexamethasone) but relapsed a year after
completion. She was then treated on an autologous stem cell
transplant and consolidative proton radiation therapy to her
mediastinum, all of which completed in January 2013, and
from which she achieved a clinical remission. In January of
2015 she presented with irregular vaginal bleeding and under-
went an exam under anesthesia, hysteroscopy, and dilatation
and curettage, where a diagnosis of endometrioid-type
endometrial cancer, grade 1, was made. She ultimately under-
went a total laparoscopic hysterectomy and bilateral salpingo-
oophorectomy, and final pathology confirmed a T1B, grade 1
endometrioid adenocarcinoma with evidence of lymphovascu-
lar invasion and positive pelvic washings. Her family history at
this time was only positive for Hodgkin’s disease and ductal
carcinoma in situ in a half-sister (who tested negative for a
BRCA mutation), breast cancer in a paternal aunt, and prostate
cancer in her maternal and paternal uncles. Prior to the
scheduled comprehensive surgical staging, she presented with
a firm and tender vaginal nodule.

Correspondence: Don S. Dizon, MD, Lifespan Cancer Institute, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. Telephone: 401-444-4538;
e-mail: don.dizon@lifespan.org Received October 10, 2017; accepted for publication January 23, 2018. http://dx.doi.org/10.1634/theoncolo-
gist.2017-0526

The Oncologist 2018;23:1–4 www.TheOncologist.com c AlphaMed Press 2018

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 Published Ahead of Print on February 22, 2018 as 10.1634/theoncologist.2017-0526.

2 Complete Remission Following Pembrolizumab

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Figure 1. Recurrence identified by Positron Emission Tomography/Computed Tomography (PET/CT). (A): Recurrence involving rectus
abdominis on right side following second surgery for node dissection and resection of a vaginal recurrence. (B): Recurrence involving the
vagina showing fluorodeoxyglucose (FDG) avidity (B1) and demonstrated on CT (B2).

In March 2015, she underwent pelvic and para-aortic
node dissection plus resection of the vaginal mass. The final
pathology showed all nodes were negative; the vaginal excision
showed endometrioid adenocarcinoma, grade 1, consistent
with metastatic disease, with loss of expression of MSH2 and
MSH6, consistent with mismatch repair (MMR) deficiency. A
month later, she was seen for consultation regarding radiation
therapy, at which time a staging positron emission tomography
(PET)/computed tomography (CT) was concerning for metastatic
disease involving her right rectus muscle (Fig. 1A) and umbilicus.
Given her prior treatments for lymphoma, she was started on
hormonal therapy using alternating courses of megestrol ace-
tate for 3 weeks followed by tamoxifen for 3 weeks, beginning
in May 2015. Unfortunately, 3 months later, she had progression
of the right rectus muscle and a second vaginal recurrence. This
was treated with radiation therapy to the abdominal wall lesion,
vagina, low pelvis, and inguinal basins, all of which completed in
November 2015. An attempt to incorporate cisplatin as a radio-
sensitizer was abandoned due to prolonged myelosuppression.
She then underwent resection of the abdominal wall lesion and
a radical posterior vulvectomy requiring plastics for reconstruc-
tion, all of which completed in January 2016.
In May 2016, she developed a symptomatic perineal lesion
that was intensely FDG avid by PET/CT (Fig. 1B1). Because the
lesion recurred following both exposure to chemotherapy
(albeit briefly) and radiation therapy, we repeated a biopsy,
which showed her tumor had dedifferentiated into a high-
grade Mullerian adenocarcinoma. Given the more aggressive
histology in this recurrence, immunohistochemical stains for
MMR proteins were repeated and confirmed loss of expression
of MSH2 and MSH6 once more, consistent with her primary
tumor. Given these findings, she was referred for genetic test-
ing and her tumors sent for genomic analysis.
MOLECULAR TUMOR BOARD
Endometrial cancer is the most common gynecologic malig-
nancy, accounting for over 60,000 newly diagnosed cases in the
U.S. [1]. Although the majority of cases present at an early
stage and can be treated with curative intent, those who pres-
ent with advanced disease, or develop metastatic or recurrent
disease, have a poorer prognosis. Although active standard
treatments have been identified in the first-line (or adjuvant
setting), to date, there are limited therapeutic options for sec-
ond- or later-line treatment of this disease. This has prompted
interest in molecular testing, particularly for women with recur-
rent, advanced, or metastatic endometrial cancers, and the uti-
lization of novel strategies and the accompanying search for
predictive biomarkers.
Genotyping and General Interpretation
Tumor genomic sequencing performed at the Center for Inte-
grated Diagnostics (Department of Pathology, Massachusetts

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 Published Ahead of Print on February 22, 2018 as 10.1634/theoncologist.2017-0526.

Dizon, Dias-Santagata, Bregar et al. 3

Figure 2. Proposed mechanism of increased sensitivity to pembrolizumab. (A): Tumor cell showing PD-L1 and MHC receptor attached to
microsatellite instability-generated neoantigen. Even in the presence of BRCA mutation-associated HRD, binding of the T-cell receptor to

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tumor-associated PD-L1 escapes immune surveillance via binding of PD-1 to PD-L1. (B): In the presence of pembrolizumab, binding of PD-
1 to PD-L1 is blocked, leading to immune-mediated cytotoxicity generated by binding of the T-cell receptor to the MHC-neoantigen com-
plex. This immune-mediated cytotoxicity may be heightened if HRD is compromised, resulting in increased apoptosis.
Abbreviations: HRD, homologous recombination deficiency; MHC, major histocompatibility complex; PD-1, programmed cell death pro-
tein 1; PD-L1, programmed death-ligand 1.

c.916C>T), and in PTEN (p.R233*, c.697C>T; p.K267fs*9,

Figure 3. Clinical and radiologic evidence of benefit on pembroli-
zumab. (A): Patient-reported pain scores during the first three
cycles of pembrolizumab. Note the dramatic resolution of pain by
C2D16. (B): Computed tomography scan after four cycles of pem-
brolizumab, showing a complete remission, which continues 13
months after start of treatment.
General Hospital) used Anchored Multiplex PCR (AMP) and
targeted mutational hotspots and exons from 91 genes (REF:
see reference section below). This analysis detected multiple
variants, including pathogenic nonsense and frameshift muta-
tions in BRCA2 (p.N1784fs*3, c.5351dupA), TP53 (p.R306*,
c.800delA), a well-described missense variant in FBXW7
(p.R465C, c.1393C>T) that results in loss of function of this
tumor suppressor, and a hotspot-activating mutation in PIK3CA
(p.R88Q, c.263G>A). Rare variants of uncertain clinical signifi-
cance included the following: TP53 p.R267W (c.799C>T),
PIK3CA p.R93Q (c.278G>A), APC p.H1349R (c.4046A>G),
ARID1A p.T1514M, and p.F2141fs*59 (c. c.4541C>T and
6420delC, respectively), and AURKA splice region variant
(c.567-4G>A). Of these 12 variants, 11 involved C>T (or G>A)
transitions or small insertions/deletions at mononucleotide
repeats, consistent with the mutational signature associated
with defective DNA mismatch repair and microsatellite-
unstable tumors.
Germline testing for BRCA1 and MSH2 was performed at
GeneDx (Comprehensive Cancer Panel and MSH2 Exons 1–7
Inversion Analysis) and detected a pathogenic deletion in
BRCA1 (p.E23Vfs*17, c.68_69delAG). This variant, also known
as BRCA1 185delAG, causes Hereditary Breast and Ovarian
Cancer Syndrome and is one of three main founder mutations
in the Ashkenazi Jewish population. Testing of the patient’s
endometrial cancer using the AMP-based genotyping assay
described above detected the BRCA1 germline variant in a
heterozygous state, with no evidence of a second hit or of
BRCA1 copy loss or loss of heterozygosity (LOH) in the tumor.
The patient was negative for germline variants in MSH2, sug-
gesting she did not have Lynch syndrome. Additional tumor
sequencing was carried out for the assessment of somatic
variants in MSH2 (ColoSeq Tumor Gene Panel, University of
Washington). The analysis detected two somatic pathogenic fra-
meshift mutations in MSH2 (p.E56Afs*10, c.161_162insCCGGG;
and p.M729Cfs*16, c.2185del) that disrupt the reading frame
and result in the insertion of a premature termination codon.
These alterations are predicted to compromise protein function
and affect DNA mismatch repair, consistent with the loss of
MSH2 expression and with the microsatellite instability observed
in the tumor.

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4 Complete Remission Following Pembrolizumab

Functional Significance of the Molecular Alteration
The Cancer Genome Atlas in endometrial cancer suggests that
the disease is quite heterogeneous, with recognition of four
distinct molecular subtypes: (a) POLE associated with mutation
in the DNA polymerase gene E marked by ultramutation;
(b) microsatellite instability (MSI) associated with mutations in
the DNA mismatch repair machinery, marked by hypermuta-
tion; (c) microsatellite stable with low level of DNA copy num-
ber changes, marked by endometrioid histology; and (d) DNA
copy number high tumors, mostly associated with serous-like
histology but also observed in 25% of high-grade endometrioid
tumors [2].
Defects in any of the key components of the DNA mismatch
repair machinery (MLH1, MSH2, MSH6, or PMS2 proteins)
leads to the accumulation of large numbers of mutations, due
to the inability of the cell to correct mismatched DNA bases
arising during replication, recombination, or DNA damage.
Microsatellites are highly repetitive sequences of DNA consist-
recombination, such as those in BRCA1 or BRCA2 [5]. Similar to
MMR-deficient tumors, mutations in BRCA also lead to a higher
mutational burden, which may also render tumor cells suscepti-
ble to immune-mediated cytotoxicity resultant from immune
checkpoint inhibitors. Sequencing data indicated that the
patient’s endometrial tumor harbored pathogenic mutations in
BRCA1 (germline) and BRCA2 (somatic). Because both variants
appear to be heterozygous, we do not anticipate complete
inactivation of either tumor suppressor. However, it is tempting
to speculate that partial loss of the two genes may result in
decreased activity of the BRCA repair pathway and further con-
tribute to the production of tumor neoantigens (Fig. 2).
Patient Update
Given the patient was not able to tolerate cisplatin as a radio-
sensitizer, the team did not feel systemic therapy was a safe
option. Unfortunately, her disease had also proven resistant to
radiation therapy, and attempts for surgical control proved inef-

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ing of mono- or polynucleotide repeats. These regions are par-
ticularly susceptible to mutation during cell division, due to
slippage of the DNA polymerase, with resulting insertion or
deletion of repeating units. Such errors are corrected by the
MMR machinery, but in tumors with defective MMR, microsa-
tellite regions incur many mutations often referred.
Clinical Significance and Utility of the Molecular
Alteration
Much has been published about the responsiveness of tumors
with MMR deficiency to immune checkpoint inhibitors, includ-
ing for women with endometrial cancer. As such, patients with
tumors harboring multiple genetic alterations that result in a
high mutational burden would experience a benefit to PD-1
blockade. Indeed, although the predictors of response to PD-1
blockade are not completely established across all tumor types,
multiple molecular determinants have been evaluated, includ-
ing PD-L1 expression, mutational burden, lymphocytic infiltra-
tion, and mutation-associated neoantigens [3]. In the seminal
paper by Diaz et al., the objective response rate among 86
patients with MMR deficiency was 53% (21% complete
responses), without discrimination of whether MMR was Lynch
or non-Lynch associated. This report ultimately led to U.S. Food
and Drug Administration approval of pembrolizumab for MSI
tumors, regardless of their site of origin [4].
Mutations involving BRCA1 and BRCA2 are associated with
homologous recombination deficiency, making them suscepti-
ble to apoptosis after exposure to chemotherapy (e.g., plati-
num agents) and other DNA-damaging agents, as well as PARP
inhibitors. However, less is known about the sensitivity to PD-1
blockade among patients with known mutations in double-
strand break DNA repair pathways involving homologous
fective. In a final attempt to treat her symptomatic disease, she
began pembrolizumab in June 2016 (2 mg/kg administered
every 3 weeks). Following one dose of treatment, she had a
30% shrinkage of her tumor on exam, and by the start of her
third cycle, her pain completely resolved (Fig. 3A). Repeat imag-
ing after four cycles showed complete resolution of her peri-
neal mass, consistent with a complete response. She remains
in remission 13 months after initiation of treatment (Fig. 3B).
CONCLUSION
We report the case of a BRCA1-mutation carrier with an aggres-
sive endometrial carcinoma. The curious occurrence of a patho-
genic BRCA2 variant in her MMR-deficient tumor might have
led to partial impairment of the BRCA repair pathway. This
combination may explain her expeditious and sustained
response to PD-1 inhibition.
AUTHOR CONTRIBUTIONS
Conception/design: Don S. Dizon, Dora Dias-Santagata, Amy Bregar, Leif Ellisen,
Michael Birrer, Marcela DelCarmen
Provision of study material or patients: Don S. Dizon, Laura Sullivan, Jennifer
Filipi, Elizabeth DiTavi, Lucy Miller, Leif Ellisen, Marcela DelCarmen
Collection and/or assembly of data: Don S. Dizon, Dora Dias-Santagata, Amy
Bregar, Laura Sullivan, Marcela DelCarmen
Data analysis and interpretation: Don S. Dizon, Dora Dias-Santagata, Leif Ellisen,
Michael Birrer
Manuscript writing: Don S. Dizon, Dora Dias-Santagata, Amy Bregar, Laura Sulli-
van, Jennifer Filipi, Elizabeth DiTavi, Lucy Miller, Leif Ellisen, Michael Birrer,
Marcela DelCarmen
Final approval of manuscript: Don S. Dizon, Dora Dias-Santagata, Amy Bregar,
Laura Sullivan, Jennifer Filipi, Elizabeth DiTavi, Lucy Miller, Leif Ellisen, Michael
Birrer, Marcela DelCarmen
DISCLOSURES
The authors indicated no financial relationships.

REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer Statistics,
2017. CA Cancer J Clin 2017;67:7–30.
2. Cancer Genome Atlas Research Network
et al. Integrated genomic characterization of
endometrial carcinoma. Nature 2013;497:67–
73.
3. Le DT, Durham JN, Smith KN et al. Mismatch
repair deficiency predicts response of solid tumors
to PD-1 blockade. Science 2017;357:409–413.
4. U.S. Food and Drug Administration. FDA grants
accelerated approval to pembrolizumab for first
tissue/site agnostic indication. Available at https://
www.fda.gov/Drugs/InformationOnDrugs/Approved
Drugs/ucm560040.htm. Accessed November 20,
2017.
5. Muggia F, Safra T. ‘BRCAness’ and its implications
for platinum action in gynecologic cancer. Anticancer
Res 2014;34:551–556.

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