Abstract
Summary
Craniopharyngiomas (CPs) are rare brain epithelial tumours arising in the suprasellar region, infiltrating adjacent areas causing visual loss, panhypopituitarism, cognitive deficits and morbid obesity. Papillary CPs (PCPs) harbour in 94% BRAF mutation cases. Two patients with PCP and BRAF V600E mutations but with different tumour status were treated with BRAF and MEK inhibitors. Case I was diagnosed with biopsy and treated for 16 months with BRAF and MEK inhibitors. After 3.5 months, there was a 50% reduction of the tumour volume, and after 13 months, the tumour volume decreased from 2220 to 90 mm3 (96%). Two months after stopping the drugs, he was treated with fractionated cranial irradiation (54 Gy). No recurrence of the PCP was recorded. Eight months after stopping the drugs, he was diagnosed with an adenocarcinoma of the oesophagus, which led to his death 12 months later. In case II, a woman had had four surgeries due to recurrences of a PCP, and a BRAF V600E mutation was confirmed. After a new recurrence measuring 14 × 12 × 18 mm, she was started on BRAF and MEK inhibitors. After 4 months of treatment, a significant decrease to 8 × 9 × 13 mm was recorded. The treatment continued for 31 months, and the MRI demonstrated a stable unchanged size including scar tissue, with a volume reduction from 633 to 483 mm3. During treatment, her visual acuity improved in her left eye from 0.05 to 0.3. After stopping the drugs, ‘watchful waiting’ with repeated MRI was decided. She is now off treatment for 25 months, without any recurrence on MRI.
Learning points
CPs are rare primary brain epithelial tumours arising in the suprasellar region from remnants of Rathke’s pouch.
CPs infiltrate adjacent areas causing visual loss, panhypopituitarism, cognitive deficits and morbid obesity.
PCPs harbour in >90% BRAF V600E mutation.
BRAF V600E mutation can successfully be treated with the combination of BRAF V600E and Mekinist inhibitors.
It is suggested that PCP patients harbouring BRAF V600E mutation should be offered BRAF V600E and Mekinist inhibitors.
Background
Craniopharyngiomas (CPs) are rare primary brain epithelial tumours arising in the suprasellar region from remnants of Rathke’s pouch. About 50% of CPs originate at the level of the third ventricle floor, within the infundibulum and/or tuber cinereum regions, including the vital hypothalamus, and expand to the third ventricle cavity. CPs are characterised by a low proliferation rate and symptoms due to mass effect and local infiltration of the surrounding tissues. There are two subtypes: adamantinomatous CPs (ACPs), seen in both children and adults, and papillary CPs (PCPs), mainly seen in adults (Bunin et al. 1998). CPs constitute 1.2–4.6% of all intracranial tumours, accounting for 0.5–2.5 new cases per million/year globally (Bunin et al. 1998, Olsson et al. 2015). Regardless of the subtype, CPs are considered ‘benign tumours’ but with local invasiveness. CPs infiltrate adjacent areas, such as optic nerves, pituitary gland, hypothalamus and the brainstem, causing visual loss, panhypopituitarism, cognitive deficits and morbid obesity (Erfurth 2020). Standard treatment includes surgical resection (trans-sphenoidal or trans-cranial approaches). Currently, subtotal resection is recommended to preserve the hypothalamus with the addition of external beam radiotherapy for residual or recurrent tumour (Müller et al. 2019). The cardiovascular mortality is high in CPs with a standard mortality ratio (SMR) of 3.21–3.5, and particularly, the cerebrovascular mortality is increased (SMR 5.1–19.4), with a higher risk in women (Bulow et al. 1998, Tomlinson et al. 2001). The 20-year-overall survival was significantly lower among CP patients with hypothalamic involvement compared to those without such involvement (Sterkenburg et al. 2015).
There are no recognised targeted or cytotoxic treatments available for ACPs, and ACPs are driven by somatic mutation in CTNNB1 gene encoding β-catenin (Apps et al. 2018, Müller et al. 2019). In contrast, a new standard of targeted therapy is being developed for PCPs (Brastianos et al. 2014). Brastianos reported that >94% of PCPs harbour the BRAF V600E mutation (Brastianos et al. 2014). Functionally, this mutation activates the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is a major intracellular signal transduction pathway that is responsible for cellular proliferation, gene expression, differentiation, mitosis, cell survival and apoptosis (Lewis et al. 1998). Experimentally, in vitro, the mutation is a driver mutation, and when BRAF V600E was ectopically expressed in fibroblast cell lines, it caused hyperstimulation of the MAPK cascade and malignant transformation (Lewis et al. 1998). In 2015, the first case report showed a dramatic response of a BRAF mutant recurrent PCP to targeted therapy with a combination of BRAF V600E and Mekinist inhibitors (BRAF–MEK inhibitors) (Brastianos et al. 2016). A small number of case reports with recurrent or progressive BRAF V600E-positive PCPs treated with BRAF inhibitors either using monotherapy with vemurafenib (Aylwin et al. 2016, Chik et al. 2021) or dabrafenib (Himes et al. 2019, Rao et al. 2019) or combined with MEK inhibitors (cobimetinib and trametinib) (Brastianos et al. 2016, Roque & Odia 2017, Rostami et al. 2017, Juratli et al. 2019, Bernstein et al. 2020, Di Stefano et al. 2020, Khaddour et al. 2020) have been reported. However, so far only a few cases were treated as neo-adjuvant patients (Juratli et al. 2019, Calvanese et al. 2022, Brastianos et al. 2023). The use of combined treatment with additional MEK inhibitor is not only enhancing tumour reduction (Flaherty et al. 2012a,b), but also reducing side effects (Flaherty et al. 2012a,b). Particularly, the MEK inhibitor reduces the development of secondary squamous cell skin carcinomas (Flaherty et al. 2012a,b).
We now present two patients with PCP and BRAF V600E mutations but with different tumour status that were treated with BRAF (dabrafenib) and MEK inhibitors (trametinib). These case reports show our new study concept of treatment with dabrafenib and trametinib in PCP patients with BRAF V600E mutation (clinical trial no. NCT05525273). After diagnosis of BRAF V600E mutation, we include PCPs as neo-adjuvant, that is, biopsy proven. The aim is to treat patients with BRAF–MEK inhibitors at least for 12 months to a maximum of tumour shrinkage or as long as there is a tumour reduction, if the drugs are well tolerated. Thereafter, an individual treatment decision is made. Options are surgery of a remnant tumour and/or suitable cranial radiotherapy or ‘watchful waiting’.
The second group includes patients with previous surgery and/or cranial radiotherapy with a new recurrence. BRAF–MEK inhibitors are suggested if a new surgery would harbour the risk of hypothalamic damage or vision problems. The combined treatment will be continued as long as there is tumour shrinkage and stopped when no further reduction is recorded. After stopping the drugs, an individual decision is made, as above.
Case I
A 53-year-old man, smoker, but healthy except for treatment of hypertension was operated for a spontaneous subdural haematoma (June 2017). In addition, a tumour of unknown origin was recorded on the MRI, measuring 17 × 13 × 17 mm (width × height × length) (Fig. 1A, B, C) retro-chiasmatically at the inferior part of the third ventricle. The pituitary was small and placed in the bottom of the sella and a cystic component suggesting an empty sella. A transcranial biopsy verified a PCP, and with immunochemistry, it was positive for BRAF V600E mutation, and membrane beta-catenin was positive. His only symptoms were headache 2–4 times a month, which was cured with paracetamol. He had no symptoms of thirst, hunger or weight changes and had no visual disturbances or hormonal dysfunction. The patient was followed by an endocrinologist with repeated hormone analyses, MRI and ophthalmological investigations. However, after 38 months, the PCP grew from 17 × 13 × 17 mm to 17 × 20 × 21 mm (Fig. 1A, B, C). Together with the neurosurgeon a decision was made to suggest medical treatment with BRAF–MEK inhibitors and the patient preferred this treatment to surgery. The main reason for this suggestion was the location of the tumour in the third ventricle, posterior to the chiasma, with possible complications of hypopituitarism, hypothalamic and visual disturbances.
MR examinations in a 53-year-old male prior to medical treatment of known craniopharyngioma. Coronar (A) and sagittal T1-weighted post-contrast (B) and T2-weighted (C) demonstrate an suprasellar well-defined contrast-enhancing lesion measuring 17 × 20 × 21 mm (LR × CC × AP). Abbreviations: AP, anterior–posterior; CC, craniocaudally (height); LR, left to right (axial).
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
After all necessary pre-treatment investigations, i.e. heart echocardiograms, blood tests, ophthalmological investigations (normal visual acuity and visual fields) and MRI, the oncologist began (November 2020) the treatment with dabrafenib (Tafinlar 150 mg BID; Novartis, Switzerland) and trametinib (Mekinist 2 mg QD; Novartis, Switzerland). Before treatment, his weight was 65 kg, body mass index (BMI) was 23.5, and fat% was 23 (normal reference 11–22%) measured with bioimpedance analyses (BIA). After 3.5 months of treatment (March 2020), the tumour volume decreased by 50% (10 × 10 × 13, Fig. 2A, B, C) as compared to before the treatment (17 × 20 × 21 mm, Fig. 1A, B, C). A further reduction in the tumour volume was recorded after 10 months of treatment to 6 × 6 × 5 mm (September 2021) (Fig. 3A, B, C). After 12 months, MRI examination demonstrated a further decrease in the lesion, now measuring 5 × 4 × 3 mm (Fig. 4A, B, C). No further reduction in the tumour volume was recorded during the following 4 months; thus, after 16 months of treatment, the drugs were stopped (April 2022). After withdrawal of treatment, his weight was 66 kg, BMI was 23.5, and BIA revealed 21.5% fat mass (normal 11–22%). Thus, the PCP volume shrank from 2220 to 90 mm3 (96%) during 12 months of treatment. Directly after discontinuing the drugs, a decision was made to treat the small remnant tumour with fractionated conventional radiotherapy (54 Gy) (May–June 2022). Gamma-knife was no option due to the proximity of the chiasm. After finalising radiotherapy, the patient was followed by the endocrinologist for hormone status and by the oncologist with repeated MRI. In October 2022, 4 months after finalising cranial radiotherapy and 8 months after stopping BRAF–MEK inhibitors, a slight anaemia was shown. About 3 months later, the patient experienced some chest tightness, which accelerated. After extensive investigations and several fine-needle punctures, an adenocarcinoma was diagnosed emanating from distal oesophagus. The patient immediately started chemotherapy and immunotherapy. However, he died 12 months later due to his malignancy.
MR examination after 14 weeks of treatment of known CP. Coronar (A) and sagittal T1-weighted post-contrast (B) and T2-weighted (C) demonstrate a significant decrease in the suprasellar contrast-enhancing lesion now measuring 10 × 10 × 13 mm (LR × CC × AP).
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
MR examination after 10 months of treatment of known CP. Coronar (A) and sagittal T1-weighted post-contrast (B) and T2-weighted (C) demonstrate a further decrease in the suprasellar contrast-enhancing lesion now measuring 6 × 6 × 5 mm (LR × CC × AP).
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
MR examination after 12 months of treatment of known CP. Coronar (A) and sagittal T1-weighted post-contrast (B) and T2-weighted (C) demonstrate a further decrease in the suprasellar contrast-enhancing lesion now measuring 5 × 4 × 3 mm (LR × CC × AP).
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
Side effects and symptoms during treatment with BRAF/MEK inhibitors
During the whole treatment period, the patient was working fulltime in his occupation as a lorry driver and had normal pituitary function, which was unchanged after stopping the treatment. In the beginning of treatment, the patient experienced slight fever (about 38°) and mild headache 2–4 days a month that was cured by paracetamol. In addition, heart enzyme proBNP increased to a maximum of 491 ng/L (normal <150 ng/L) but normalised during treatment and stayed normal thereafter. He suffered from anterior uveitis in both eyes in November 2021 and then again in June 2022. During both episodes, he was treated for two months with topical corticosteroids. Thereafter, his uveitis was healed and visual function returned to normal.
Case II
A woman, currently 61 years old, had had four surgeries due to recurrences of a PCP. During 2017, she had two surgeries, and two more during 2018 and 2019, respectively. She suffered from panhypopituitarism, including diabetes insipidus, and was on substitution for all pituitary hormones except the growth hormone. Retrospective analyses of specimens showed a PCP with the BRAF V600E mutation. Before the first surgery, her vision was affected on her left eye, which improved slightly after operation, but then again worsened due to compression of the optic pathway from new recurrences of the tumour. After the fourth surgery, the chiasm was affected and was displaced inferiorly by postoperative scarring. Thus, she suffered from severely reduced visual acuity in her left eye (0.05) and visual field defects, i.e. bitemporal hemianopsia, but had normal vision in her right eye. In this case, no cranial radiotherapy was suggested due to the tumour’s proximity to the chiasm although fractionated radiotherapy would have been possible. In September 2019, a new PCP recurrence was shown, measuring 14 × 12 × 18 mm (Fig. 5A, B, C). A fifth surgery was rejected by the neurosurgeon due to the substantial risks associated with repeated surgeries. Cranial radiotherapy was not a good option due to the proximity of the chiasm. A decision was made to treat with dabrafenib 150 mg BID and trametinib 2 mg QD. After 4 months of treatment, the partially cystic PCP demonstrated a significant decrease, now measuring 8 × 9 × 13 mm (Fig. 6A, B, C). MRI examination after 10 months of treatment demonstrated a further slightly reduced suprasellar contrast-enhancing lesion now measuring 8 × 9 × 11 mm (Fig. 7A, B, C). The treatment continued for 31 months, and the MRI demonstrated a stable unchanged size of the suprasellar lesion now measuring 8 × 8 × 11 mm (Fig. 8A, B, C). During the treatment period, the tumour decreased in volume from 633 to 483 mm3; however, scar tissue made the exact measurement of the tumour from surrounding scar tissue more difficult. As no further reduction of the tumour was recorded, the drugs were discontinued (March 2022). During the treatment, her visual acuity improved in her left eye from 0.05 to 0.3. After stopping the drugs, a decision was made of ‘watchful waiting’ with repeated MRI (every third month for the first year and then every sixth month) as no neurosurgery or cranial radiotherapy was suggested due to the tumour location. She is now off treatment since 25 months, without any recurrence shown on MRI.
MR examination in a 60-year-old female prior to medical treatment of known partially cystic CP.
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
MR examination after 16 weeks of treatment of known partially cystic CP. Coronar (A) and sagittal T1-weighted post-contrast (B) and T2-weighted (C) demonstrate a significant decrease in the suprasellar lesion now measuring 8 × 9 × 13 mm (LR × CC × AP).
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
MR examination after 10 months of treatment of known partially CP.
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
MR examination after 31 months of treatment of known partially CP.
Citation: Endocrine Oncology 4, 1; 10.1530/EO-24-0024
Side effects and symptoms during treatment with BRAF/MEK inhibitors
She experienced some stomach problems, which stopped after discontinuation of treatment. An increase in the cardiac enzyme proBNP was recorded to a maximum of 362 ng/L (normal reference <150 ng/L), which returned to normal during treatment.
Discussion
In both cases, the drugs were successful in reducing the PCP volume. In the neo-adjuvant case (case I), an almost complete volume reduction was achieved, and in case II, a substantial volume reduction was recorded together with improvement of vision. In accordance with previous case reports using the combination of BRAF–MEK inhibitors (Brastianos et al. 2016, Roque & Odia 2017, Rostami et al. 2017, Juratli et al. 2019, Bernstein et al. 2020, Khaddour et al. 2020) or with BRAF inhibitors alone (Aylwin et al. 2016, Himes et al. 2019, Rao et al. 2019, Chik et al. 2021), a rather rapid effect in reducing the PCP volume was shown. In both our cases, the most obvious reduction of tumour volume was recorded during the first 3–4 months, and thereafter, only a slight further reduction was shown. For safety or consolidation reasons, additional months of treatment were added.
Early in the development of BRAF inhibitors, treatment-associated cutaneous squamous cell carcinoma (SCC) raised concerns regarding oncogenic risks. In phase II trials of BRAF inhibitors, 10–26% of patients developed cutaneous SCC or keratoacanthoma (Ascierto et al. 2013). Molecular characterisation of these SCCs found that some tumours harboured H-RAS mutations (Oberholzer et al. 2012). All mammalian cells express three closely related RAS proteins, H-RAS, K-RAS and N-RAS, that promote oncogenesis when mutationally activated at codons 12, 13 or 61. Despite a high degree of similarity between the isoforms, K-RAS mutations are far more frequently observed in cancer and each isoform displays preferential coupling to particular cancer types. Reports of the progression of a pre-existing N-RAS mutant chronic myelomonocytic leukaemia in a melanoma patient treated with vemurafenib (Callahan et al. 2012), the progression of a K-RAS mutant colon cancer (Andrews et al. 2013) and the progression a K-RAS mutant pancreatic cancer (Carlino et al. 2015) in two separate patients treated with combined BRAF and MEK inhibition (dabrafenib and trametinib) underscore this possibility. Thus, if RAS mutation is present, there is a slight risk of RAS-driven secondary malignancy. In case I, later suffering from an adenocarcinoma, DNA was extracted from formalin-fixed and paraffin-embedded tissue sections of distal oesophagus with adenocarcinoma and was sequenced. RAS mutations were not present in the tumour, thus considered unrelated to the treatment.
In case II, the tumour remnant was embedded in contrast-enhancing scar tissue that made the evaluation and exact measurement of the tumour from surrounding scar tissue more difficult. Again, the most remarkable tumour volume reduction was shown during the first 4 months of treatment. The treatment went on mainly for consolidation treatment because this PCP showed so many recurrences and that the drugs were well tolerated by the patient.
With three exceptions (Juratli et al. 2019, Calvanese et al. 2022, Brastianos et al. 2023), previous case reports on the dual treatment of BRAF and MEK inhibitors all included patients with repeat operations and in some cases together with cranial radiotherapy. In the work of Juratli et al. (2019), a 21-year-old male had symptoms of an invasive CP (weight gain, nausea and visual field deficits) with an enhancing suprasellar mass. The diagnostic procedure with biopsy was, however, complicated by infarcts, involving the right choroidal artery territory and causing panhypopituitarism. One month after the operation, imaging revealed continued tumour growth, and he was started on dabrafenib and trametinib. Serial MRI scans showed a significant reduction in the tumour size, approximately 80–90% reduction over a course of 6 months, corresponding to improvements of his mental status and headaches. Our patient (case I) was in fact the first showing a PCP invading the third ventricle in proximity to the chiasm that was almost abolished without surgery and that left pituitary–hypothalamic function and vision intact, after 16 months of treatment. A very recent single-group study on 16 PCP patients and BRAF mutation was published (Brastianos et al. 2023). Fifteen of the 16 patients had partial response or better to the BRAF–MEK inhibitor combination vemurafenib–cobimetinib. The status of the primary tumour was either subtotal resection (nine patients) or complete resection with recurrence (three patients). Biopsy was performed only in four patients, but separate results on this subset were not reported (Brastianos et al. 2023).
In conclusion, our first experience in BRAF and MEK inhibitors was successful in reducing the tumour mass in both a neo-adjuvant and an adjuvant patient. An almost total reduction in the neo-adjuvant patient was recorded, leaving an intact hypothalamic–pituitary function. Partial reduction was shown in the adjuvant patient, together with improvement of visual acuity. Uncertainty remains concerning optimal timing and whether single-agent (BRAF V600E inhibitors) or dual therapy (+MEK inhibitors) should be used as the duration of treatment. In addition, diagnostic approaches including analyses of BRAF mutation markers in blood might be helpful, with additional use of monitoring treatment response (Brastianos et al. 2016).
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
EME wrote the manuscript and was involved in the patients’ care. SK was involved in the patients’ care and reviewed the manuscript. PCS analysed the MRI and reviewed the manuscript. PS and BH were involved in the patients’ care and reviewed the manuscript.
Patient consent
Written informed consent for case I was obtained from his son and for case II from the patient for publication of the submitted article and accompanying images.
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