PMC7446515_01
Exceptional response in patient with germline PTEN R130Q mutation. (A) Germline PTEN mutation c.389G>A, pR130Q. CDC14, phosphatase domain. Illustration from https://proteinpaint.stjude.org. (B) Immunohistochemistry demonstrating (i) absent PTEN staining in the tumor and (ii) cytoplasmic and membranous expression of pAKT in the 40% of tumor cells. (C) Computed tomography (CT) scans during the patient's time on capivasertib, with white arrows indicating axillary disease: (i), September 2015, baseline CT showing two areas of axillary lymphadenopathy; (ii) January 2016, CT scans demonstrating partial response following 4 months of carboplatin-paclitaxel-bevacizumab chemotherapy; and (iii) December 2016, CT scans following 11 months of capivasertib monotherapy demonstrating persistent complete response before progression in February 2017.
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fig1
After enrolling in SAFIR02 (ClinicalTrials.gov identifier: NCT02299999), targeted panel sequencing (Ion Torrent PGM; Thermo Fisher Scientific, Villebon, France) of a fresh tumor biopsy sample revealed the presence of a heterozygous germline PTEN mutation (c.389G>A, p.R130Q, SNP rs121909229) alongside other variants (Fig 1A; Data Supplement). Immunohistochemistry revealed lack of PTEN expression in the tumor (Fig 1B). Upon completion of chemotherapy, tumor evaluation demonstrated a partial response (by RECIST, version 1.1) with 60% reduction of target lesions (Fig 1C).
PMC7446515_02
Exceptional response in patient with germline PTEN L23X mutation. (A) Germline PTEN mutation c.T68G:p.L23X. CDC14, phosphatase domain. Illustration from https://proteinpaint.stjude.org. (B) PTEN immunohistochemistry from (i) control tissue and (ii) noncancerous and (iii and iv) tumor-containing lymph node. The control tissue shows mainly cytoplasmic expression of PTEN. The noncancerous lymph node and the residual lymphatic tissue in the lymph node metastasis also show a PTEN expression comparable with the control. The tumor cells in the lymph node metastasis display weaker PTEN staining, which is mainly nucleolar. (C) Computed tomography (CT) scans during the patient's time on capivasertib, with white arrows indicating disease in the liver: (i) October 2012, baseline CT demonstrating a liver deposit; (ii) January 2013, CT following two cycles of paclitaxel and capivasertib; (iii) CT demonstrating continued complete response on maintenance capivasertib 7 months after cessation of paclitaxel; and (iv) May 2014, final CT before progression June 2014.
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PTEN mutation (exon 1, c.T264A:p.Y88X) with an allele frequency (AF) of 25.5%, alongside other variants (Fig 2A; Data Supplement). PTEN immunohistochemistry revealed reduced PTEN staining in the tumor (Fig 2B). Postoperative staging revealed metastatic disease with mediastinal lymph node and lung metastases. She had a confirmed maintained response in May 2014 until progression occurred in June 2014:a progression-free survival of 19 months:and a maintained complete response for 12 months on capivasertib alone (Fig 2C).