Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1-Deficient Carcinoma
Abstract
Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non- Fermentable-related matrix-associated actin-dependent reg- ulator of chromatin subfamily B member 1 gene (SMARCB1) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI- 1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next-generation-sequencing-based targeted cancer-related gene assay con- firmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single-patient expanded-use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI-1-deficient tumors, war- ranting further evaluation in clinical studies. The Oncologist 2019;24:146–150
A 30-year-old never-smoker female with no significant medical history initially presented with dry cough and hemoptysis. Her family history was also not significant for cancer, other than colon cancer of her paternal grandfather at age 70. Computed tomography (CT) imaging showed a 4.9-cm suprahilar mass in her left lung with mediastinal lymphadenopathy and suspicious bone lesions. Subsequent biopsy with mediastinoscopy showed poorly differentiated non-small cell carcinoma with rhabdoid features andoccasional psammoma bodies. Immunostaining revealed that the tumor was positive for AE1/AE3, Cam5.2, p40, and PAX-8, focally positive for calponin, and negative for TTF-1, chromogranin, synaptophysin, NUT-1, CD99, CD5, cKIT, and S100. Brahma-related gene 1 (encoded by the WI/SNF-related matrix-associated actin-dependent regula- tor of chromatin subfamily A member 4 gene [SMARCA4]) immunostaining showed nuclear retention, and integrase interactor 1 (INI-1; encoded by the SWItch/SucroseCorrespondence: Hyunseok Kang, M.D., Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, 1600 Divisadero Street, UCSF Box 1770, San Francisco, California 94115, USA. E-mail: [email protected] Received May 8, 2018; accepted for publication August 20, 2018; published Online First on October 8, 2018. http://dx.doi.org/10.1634/theoncologist.2018-0279Non-Fermentable [SWI/SNF]-related matrix-associated actin- dependent regulator of chromatin subfamily B member 1 gene [SMARCB1]) staining showed loss of nuclear expres- sion (Fig. 1).
Because of the cytokeratin positivity, rhabdoid features, and loss of INI-1 expression, the tumor was classi- fied as an INI-1-deficient carcinoma. Positron emission tomography (PET)-CT revealed hypermetabolic precarinal and prevascular lymphadenopathy along with hypermeta- bolic foci in the patient’s sixth rib and lumbar vertebral bod- ies consistent with metastatic bone disease. CT-guided biopsy of the L1 vertebra confirmed the presence of meta- static poorly differentiated carcinoma. The patient received three cycles of docetaxel, cisplatin, and 5-FU (TPF) for rap- idly progressing disease and achieved partial response. She chose to enroll in a phase II clinical trial of the enhancer of zeste homolog 2 (EZH2) inhibitor tazemetostat (NCT02601950). Unfortunately, 4 months later, her disease progressed, causing complete atelectasis of left upper lobe. Additional cycles of TPF were attempted, but she pro- gressed rapidly through the treatment. Subsequently, she underwent surgical debulking of the tumor in her lung followed by radiotherapy for palliation of respiratory symptoms. A next-generation-sequencing-based genomic profiling test in a Clinical Laboratory Improvement Amendments-certified laboratory (Foundation Medicine Inc, Cambridge, MA) was performed to get guidance on next line of treatment, and the result showed loss of SMARCB1, which encodes INI-1, breast cancer 1 gene (BRCA1) mutation (C61G), and checkpoint kinase 2 gene (CHEK2) truncation at intron 2.INI-1-Deficient CarcinomaSMARCB1 encodes INI-1, which is a core subunit protein of the SWI/SNF ATP-dependent chromatin remodeling com- plex [1]. SMARCB1 is a known tumor suppressor gene and has been implicated in chromatin remodeling and tran- scription regulation [2]. INI-1 is ubiquitously expressed in the nuclei of all normal cells, and loss of expression of INI- 1 in the nuclei has been a wide range of epithelial and mesenchymal tumors. Loss of SMARBC1 is the defining genetic alteration seen in epithelioid sarcomas [3], rhab- doid tumors of childhood [4], and SMARCB1-deficient sino- nasal carcinomas [5].
However, INI-1 loss can also be seen in a less well-defined cohort of other poorly differentiated carcinomas that tend to have basaloid or rhabdoid mor- phology and follow an aggressive course; these carcinomas have been reported at a wide range of anatomic sites including the kidney [6] and gastrointestinal tract [7]. INI-1 loss specifically has not been well characterized in lung cancers. A series of 316 patients with non-small cell lung cancer demonstrated no cases with INI-1 loss while reveal- ing infrequent losses in other SWI/SNF complex proteins SMARCA2 and SMARCA4 [8]. Lung tumors with basaloid or rhabdoid morphology have not undergone systematic anal- ysis for INI-1 alterations [9]. Differentiation between these tumor types requires consideration of not only INI-1 loss but a wide range of other clinicopathologic features. No systemic chemotherapy has yet demonstrated significant benefit for patients with metastatic INI-1-deficient carcino- mas. A recent report suggested activity of an EZH2inhibitor, tazemetostat, in INI-1-deficient tumors of pediat- ric patients [10], and the agent is being investigated in adult patients with various INI-1-deficient tumors as well [11]. However, there is no established therapy for this rare, aggressive disease yet.Molecular Findings and ImplicationsThe case was discussed at our institution’s molecular tumor board. Interestingly, clinical genomic profiling of our patient’s tumor revealed the presence of a pathogenic C61G mutation of the BRCA1 gene, which affects the ubi- quitin ligase function of the really interesting new gene (RING) domain and reduces heterodimerization of BRCA1 and BRCA1-associated RING domain protein 1 [12]. Unlike other deleterious BRCA1 mutations, this missense mutation was not associated with sensitivity to cisplatin or poly (ADP-ribose) polymerase inhibitors in a preclinical model [13]. The variant allele fraction of the BRCA1 mutation was 48%, which is suggestive of a heterozygous germline vari- ant, and the patients test results were positive for the germline mutation of BRCA1 C61G (NantOmics, Culver City, CA).
Retention of a normal BRCA1 allele and the nature of the mutation affecting the RING domain may explain why our patient did respond to initial platinum-based chemo- therapy but quickly developed resistance later. The tumor also harbored a truncation in intron 2 of CHEK2, which is predicted to be inactivating, and has been reported to be associated with increased risk of breast cancer [14]. CHEK2 encodes for checkpoint kinase 2, a serine/threonine kinase that plays a key role in the DNA damage response [15].SWI/SNF and Polycomb complexes have antagonistic development roles, and INI-1 loss leads to upregulation of EZH2, leading to increased histone H3 on lysine 27-trimethylation in INI-1-deficient tumors and upregula- tion of stem-cell-associated programs [16], which are con- sistent with the dedifferentiated phenotype of these cancers. INI-1-deficient tumors are shown to be sensitive to EZH2 inhibition in preclinical studies [17], and early- phase clinical trials demonstrated promising activity of an EZH2 inhibitor in patients with these tumors. Preliminary data showed that tazemetostat led to partial response in 4 and stable disease in 2 out of 31 patients to date, with 13 patients still on treatment [11]. The only known mecha- nism implicated in the development of resistance to EZH2 inhibitors is the development of secondary mutations [18], but preclinical studies evaluating other possible mecha- nisms are ongoing.Recent studies have highlighted other oncogenic signal- ing pathways that are de-repressed in the setting of INI-1 deficiency, including MYC and aurora A kinase (AurkA) [19]. AurkA regulates the formation and stability of the mitotic spindle during the cell cycle, is implicated in p53 degrada- tion, and is upregulated in a variety of malignancies, repre- senting a promising therapeutic target [20].
Microarray data show that re-expression of INI-1 in rhabdoid tumors leads to downregulation of AurkA [21]. Lee et al. showed that SWI/SNF associates with the promoter of AURKA, gene encoding AurkA, repressing its expression particularly in rhabdoid tumor cells, whereas knockdown of AURKA induces mitotic arrest and apoptosis in these cells but notin normal cells [19]. Of note, non-small cell lung cancer cells harboring mutations of SMARCA4, another critical component of the SWI/SNF complex, are particularly sensi- tive to AurkA inhibition [22]. Figure 2 represents the onco- genic signaling involving SWI/SNF complex in cancer cells providing targeted therapy opportunities.Given these encouraging preclinical findings, AurkA inhibition has been introduced to the clinical setting forin four children with recurrent or progressive atypical tera- toid/rhabdoid tumors with INI-1 deficiency, demonstrating stable disease or disease regression in all four patients, with two patients having stable disease regression for 1 and 2 years on therapy [24]. Based on these findings, the board recommended to use an AurkA inhibitor such as alisertib.patients with INI-1-deficient tumors. Alisertib is a novel AurkA inhibitor, having been evaluated in early-phase clini- cal trials for nongenomically selected malignancies such as sarcomas [23]. Wetmore et al. reported the use of alisertibAlisertib use was reviewed and approved by the institu- tional review board, after being granted a single-patientexpanded use by the U.S. Food and Drug Administration. The patient started alisertib 50 mg twice daily on days 1–7 every 21 days after signing the informed consent. After six cycles, her left upper lobe lesion decreased by 25%, and the rest of the disease remained stable. Her disease pro- gressed with a new enhancing lung nodule after eight cycles, but her index lesion and the rest of the lesions remained stable (Fig. 3). She chose to stay on the treat- ment given the lack of therapeutic options. After 10 cycles, the new lesion continued to grow and the treatment was held for palliative radiation. She received two additional cycles after radiation, while looking for other treatment options, but her disease continued to progress. She toler- ated the treatment well except for oral ulcers between days 7 and 10 of each cycle and two treatment delays from nonfebrile neutropenia. Her progression-free survival was 6 months.
CONCLUSION
This case illustrates the potential role of an ArukA inhibitor for INI-1-deficient carcinoma even after progression on another promising targeted therapy modality, EZH2 inhibition. Our patient started on alisertib and remained stable for 6 months, which was not expected at the time of treat- ment initiation, given her rapid progression on combination chemotherapy and the EZH2 inhibitor, tazemetostat. She tolerated the treatment well, without significant side effects, and was maintained on the agent for 7.4 months pathologic and genomic information in order to provide a personalized treatment offering significant clinical benefit to a patient with a rare and aggressive type of cancer. Finally, the course of our patient, along with preclinical Alisertib data, supports that AurkA inhibition may have an impor- tant role in the management of patients with INI- 1-deficient tumors, warranting further evaluation in clinical studies.