An 81-year-old woman was initially diagnosed with left-breast, triple-negative invasive ductal carcinoma Nottingham grade 2 (American Joint Committee on Cancer [AJCC] stage pT1cN01) 4 years before the case was discussed by the molecular tumor board. She underwent left-breast lumpectomy and adjuvant radiation therapy. A local recurrence was resected 3 months later. One year later, endometrial adenocarcinoma, endometrioid type International Federation of Gynecology and Obstetrics grade 2 (FIGO; stage II1) was diagnosed and treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by postoperative external beam radiotherapy and high-dose vaginal brachytherapy. Immunohistologic studies for DNA mismatch repair proteins on the endometrial adenocarcinoma revealed loss of expression of MLH1 and PMS2, and MLH1 promoter hypermethylation analysis was positive.

Another year later, positron emission tomography–computed tomography scans indicated bilateral lung metastases suggestive of metastatic endometrial adenocarcinoma and a left axillary hypermetabolic lymph node suggestive of metastatic breast adenocarcinoma (estrogen-receptor negative, progesterone-receptor negative [1+, 10%], and HER2 negative). She underwent nanoparticle albumin-bound–paclitaxel therapy for pulmonary disease burden with pulmonary disease progression and tamoxifen plus megastrol acetate for treatment of her metastatic endometrial cancer. Two years later, new subcutaneous chest wall and scalp lesions were noted. A biopsy specimen was taken of the chest wall lesion, which was found to be consistent with metastatic carcinoma most likely of breast origin, based on immunohistochemical and clinical findings. Follow-up magnetic resonance imaging testing showed metastases to bone and brain.

Because of systemic progression, tumor molecular profiling for one of the chest wall lesions was performed using the Stanford Actionable Mutation Panel (STAMP) assay, which is a 198-gene, hybrid-capture–based, solid-tumor, next-generation sequencing panel. STAMP testing detected the following genomic alterations: pathogenic missense mutations in CTNNB1, PIK3CA, and PTEN. The case was discussed by the molecular tumor board; the molecular profiling was considered to be suggestive of endometrial origin rather than breast origin. Given that the primary endometrial adenocarcinoma had been microsatellite unstable, microsatellite instability (MSI) testing was recommended on the metastasis to enable the potential use of immune-checkpoint inhibitors, if positive. MSI testing by polymerase chain reaction demonstrated that the tumor was MSI high.

After liposomal doxorubicin chemotherapy, stereotactic radiotherapy for the brain metastases, and palliative radiation therapy to a painful right acetabulum metastasis, the patient started treatment with pembrolizumab on a compassionate-use basis because she did not qualify for current open trials (having two active cancers), and this was before Food and Drug Administration approval of immunotherapies for MSI tumors. She had an immediate symptomatic and imaging-based response after the first cycle, and since beginning treatment has received 28 cycles of pembrolizumab over 18 months. Positron emission tomography–computed tomography scans have shown stable or decreased size of all lesions excluding her lung metastases. Stereotactic radiotherapy was delivered to the lung lesion with response. She is tolerating therapy well except for some lower extremity bullous skin lesions controlled with local efforts.

Given the challenging patient clinical history, we reviewed the most common mutations in ductal and endometrioid adenocarcinoma in the Catalogue of Somatic Mutations in Cancer (COSMIC)2 (version 84) to understand recurrent mutational signatures present in both malignancies. Table 1 summarizes the three pathogenic variants from the patient’s chest wall metastasis. The PTEN, PIK3CA, and CTNNB1 variants resulted in predicted deleterious alterations at relatively high allele fractions (86%, 42%, and 41%, respectively (tumor percentage estimated by a pathologist to be 70%). Table 2 lists the top 10 mutated genes in endometrioid adenocarcinoma and breast ductal adenocarcinoma. Notably, both malignancies commonly harbor PTEN and PIK3CA mutations. Hence, although nonspecific, the β-catenin (CTNNB1) somatic mutation (as opposed to an amplification) is virtually never seen in ductal breast carcinoma and thus was a unique finding suggesting that the molecular signature of the biopsy specimen was more consistent with an endometrial adenocarcinoma origin than that of a breast adenocarcinoma.


Table 1. Summary of Identified Somatic Variants From the Chest Wall Lesion, Allele Fractions, and Clinical Variant Pathogenicity Interpretation (Percent Tumor, 70%)


Table 2. Top 10 Mutated Genes in Endometrioid and Ductal Adenocarcinomas in COSMIC2

To more convincingly distinguish the tissue of origin of the patient’s metastatic disease, the molecular tumor board members recommended testing of mismatch repair protein status by polymerase chain reaction and agreed that if the tumor demonstrated microsatellite instability, the patient would be eligible to receive pembrolizumab as a participant in a local clinical trial or off label (this was before the Food and Drug Administration approval of pembrolizumab for MSI-high tumors).

Discussion of possible alternatives to immune-checkpoint inhibitors included therapeutic routes focused on targeting the AKT-mTOR pathway, because of PTEN and PIK3CA mutations. Clinical trials with PI3K inhibitor monotherapy have seen limited efficacy,3 whereas AKT and mTOR inhibitors for PTEN-mutated cancers have demonstrated stable disease burden.4 Yet, patients with recurrent endometroid carcinoma and CTNBB1 mutations have responded well to combination lentrozole and everolimus therapy.5 However, a separate attribute of PTEN-mutated endometrioid cancers is that approximately 40% of cases are known to have high MSI status, which has been demonstrated to respond to immunotherapy.6

© 2018 by American Society of Clinical Oncology

Conception and design: Helio A. Costa, Rochelle Reyes, Meredith Mills, James L. Zehnder, James M. Ford, Carlos J Suarez

Administrative support: Meredith Mills, James M. Ford, Carlos J Suarez

Provision of study material or patients: Rochelle Reyes, George Sledge, James M. Ford, Carlos J Suarez

Collection and assembly of data: Helio A. Costa, Meredith Mills, James L. Zehnder, James M. Ford, Carlos J Suarez

Data analysis and interpretation: Helio A. Costa, Meredith Mills, George Sledge, Christina Curtis, James M. Ford, Carlos J Suarez

Manuscript writing: All authors

Final approval of manuscript: All authors

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to or

Helio A. Costa

Research Funding: Dovetail Genomics (Inst)

Consulting or Advisory Role: Gerson Lehrman Group

Rochelle Reyes

No relationship to disclose

Meredith Mills

Research Funding: Myriad Genetics (Inst)

Recipient: Natera (Inst)

James L. Zehnder

No relationship to disclose

George Sledge

Leadership: Syndax

Stock and Other Ownership Interests: Syndax

Honoraria: Symphony Evolution

Consulting or Advisory Role: Symphony Evolution, Coherus Biosciences, Radius Health, Peregrine Pharmaceuticals, Taiho Pharmaceutical

Research Funding: Roche (Inst)

Travel, Accommodations, Expenses: Radius Health, Taiho Pharmaceutical

Christina Curtis

Consulting or Advisory Role: GRAIL

James M. Ford

No relationship to disclose

Carlos J. Suarez

No relationship to disclose

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DOI: 10.1200/PO.18.00177 JCO Precision Oncology - published online September 19, 2018

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