{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T12:38:25Z","timestamp":1771677505696,"version":"3.50.1"},"reference-count":49,"publisher":"Harborside Press, LLC","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>A woman with estrogen\/progesterone receptor\u2013positive, <jats:italic>ERBB2<\/jats:italic>-negative metastatic breast cancer developed progressive disease despite treatment with multiple hormonal and chemotherapeutic modalities. She carried a germline variant of <jats:italic>MLH1<\/jats:italic> (1835del3), also known as c.1835_1837del and v612del, the pathogenicity of which has not been conclusively determined. <jats:italic>MLH1<\/jats:italic> staining was not seen on immunohistochemical staining of her tumor tissue. The patient experienced a &gt;5-year dramatic response to 4 doses of pembrolizumab. Family studies revealed multiple other relatives with the <jats:italic>MLH1<\/jats:italic> 1835del3 variant, as well as multiple relatives with colon cancer. The one relative with colon cancer who underwent genetic testing demonstrated the same variant. Laboratory studies revealed that the patient\u2019s tumor showed loss of heterozygosity (LOH) in the <jats:italic>MLH1<\/jats:italic> region, high levels of microsatellite instability, and a high tumor mutational burden. LOH in the <jats:italic>MLH1<\/jats:italic> region, along with the remarkable clinical response to pembrolizumab treatment and the presence of the same <jats:italic>MLH1<\/jats:italic> variant in affected relatives, supports the hypothesis that the <jats:italic>MLH1<\/jats:italic> 1835del3 variant is pathogenic. Given the patient\u2019s family history, this likely represents an uncommon presentation of Lynch syndrome. Physicians should be alert to evaluate patients for targetable genetic variants even in unlikely clinical situations such as the one described here.<\/jats:p>","DOI":"10.6004\/jnccn.2023.7035","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T14:49:53Z","timestamp":1693320593000},"page":"1110-1116","source":"Crossref","is-referenced-by-count":2,"title":["Hormone Receptor\u2013Positive Breast Cancer Sensitive to Pembrolizumab: Evidence of the Pathogenicity of the MLH1 Variant 1835del3"],"prefix":"10.6004","volume":"21","author":[{"given":"Henry G.","family":"Kaplan","sequence":"first","affiliation":[{"name":"Swedish Cancer Institute, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey R.","family":"Whiteaker","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brianna","family":"Nelson","sequence":"additional","affiliation":[{"name":"Swedish Cancer Institute, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard G.","family":"Ivey","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Travis D.","family":"Lorentzen","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uliana","family":"Voytovich","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Corwin","sequence":"additional","affiliation":[{"name":"CellNetix, Tukwila, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Resta","sequence":"additional","affiliation":[{"name":"Swedish Cancer Institute, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda G.","family":"Paulovich","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4047","reference":[{"key":"B1","series-title":"N Engl J Med","first-page":"217","article-title":"Pembrolizumab plus chemotherapy in advanced triple negative breast cancer","volume":"387","author":"Cortes J","year":"2022","unstructured":"Cortes J, Rugo HS, Cescon DW,  Pembrolizumab plus chemotherapy in advanced triple negative breast cancer. 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