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Brief Communications
B R I E F C O M M U N I C AT I O N S
Progression of KRAS mutant pancreatic adenocarcinoma during vemurafenib treatment in a patient with metastatic melanoma A. Grey,1 A. Cooper,1 C. McNeil,1 S. O’Toole,2 J. Thompson1 and P. Grimison1 1
Sydney Cancer Centre and 2Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
Key words vemurafenib, BRAF inhibitor, melanoma, secondary malignancy, pancreatic adenocarcinoma. Correspondence Peter Grimison, Chris O’Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia. Email: [email protected]
Abstract Vemurafenib is a tyrosine kinase inhibitor of BRAF that prolongs survival in patients with BRAF V600-mutant metastatic melanoma. Secondary cutaneous malignancies are a well-documented toxicity of vemurafenib, thought to be mediated by enhanced ERK signalling in BRAF wild-type, RAS-mutant cells. Vemurafenib could also promote growth of non-cutaneous secondary malignancies by a similar mechanism. We present a case of an individual who received vemurafenib for metastatic melanoma and experienced rapid growth of a pre-existing KRAS-mutant pancreatic adenocarcinoma.
Received 2 October 2013; accepted 27 November 2013. doi:10.1111/imj.12415
A previously well 44-year–old man presented in 2006 with a primary cutaneous melanoma on his left neck, which was resected. Two years later, he developed stage M1a disease associated with multiple small intracutaneous metastases predominantly involving the scalp and neck. There was no evidence of visceral involvement on a staging computed tomography (CT) scan. Subsequent mutation testing on a resected intracutaneous metastasis revealed a BRAF V600E mutation. The patient’s cutaneous metastases were successfully treated with topical diphencyprone, and he subsequently went into complete remission. Six years after his initial diagnosis, the patient presented to hospital with several weeks of increasing epigastric pain, nausea, anorexia and weight loss. On examination, he was jaundiced. Liver function tests were deranged in an obstructive pattern. A CT scan of the abdomen revealed a 2.6-cm hypodense infiltrative mass
Funding: None. Conflict of interest: S. O’Toole reports personal fees from Pfizer Australia, Roche Australia and Lilly Oncology, and non-financial support from Roche, all outside the current article. J. Thompson reports personal fees from Provectus and GlaxoSmithKline, outside the current article. C. McNeil is a Roche Advisory Board Member (non-funded). © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
involving the pancreatic uncinate process with associated pancreatic and extrahepatic biliary dilatation. Positron emission tomography-CT (PET-CT) demonstrated uptake in the vicinity of the pancreatic uncinate process, as well as in porta hepatis, right pelvic and iliac lymph nodes. Given his previous diagnosis of stage M1a disease, this pattern on PET was felt most likely to represent metastatic melanoma. The patient underwent emergency therapeutic endoscopic retrograde cholangiopancreatography and biliary stenting of a distal common bile duct stricture. Post-procedure, the patient’s abdominal pain, jaundice and liver function tests improved. One week later, the patient was commenced on vemurafenib at a dose of 960 mg twice daily orally. This was later reduced to 720 mg twice daily when he developed a rash. Two weeks after starting vemurafenib, a repeat PET-CT scan revealed surprising, and mixed, results. There was decreased metabolism in the right pelvic, internal and common iliac nodes, suggestive of a response to vemurafenib. However, the pancreatic lesion was significantly larger, more necrotic and more glucose avid. This raised the suspicion of two separate malignancies: metastatic melanoma, which had responded to vemurafenib, and a primary pancreatic malignancy, which had rapidly progressed during vemurafenib treatment. Cytology from percutaneous fine needle aspiration 597
Brief Communications
of the pancreatic mass was consistent with a primary pancreatic adenocarcinoma. A restaging CT scan at 6 weeks after initial presentation to hospital showed a 6-cm locally advanced pancreatic cancer encasing the common bile duct and involving between 90 and 180 degrees of the superior mesenteric artery, and a new 7-mm hypodensity within segment eight of the liver that could represent a solitary metastasis, but which was not anatomically amenable to biopsy. In view of the rapid growth of the pancreatic adenocarcinoma, and the relatively indolent course of the metastatic melanoma, it was decided to proceed with concurrent chemoradiotherapy (using oral capecitabine) to the pancreas. The aims of treatment were to downstage the tumour, which could prevent local symptoms and prolong survival. Vemurafenib was ceased, given its unknown safety profile in combination with capecitabine-based chemoradiotherapy and because of concerns that the rapid growth of the pancreatic lesion may have been potentiated by vemurafenib therapy. Following completion of chemoradiotherapy, it was planned to restage both diseases and to consider further therapy directed at either the pancreatic cancer or melanoma. A restaging CT scan following 4 weeks of combined chemoradiotherapy revealed development of multiple hepatic lesions suspicious for metastases. Percutaneous liver biopsy demonstrated metastatic pancreatic adenocarcinoma rather than metastatic melanoma, which was positive for a KRASQ61L mutation. There was no evidence on follow-up CT scans to suggest progression of his metastatic melanoma within intra-abdominal or pelvic lymph nodes. The patient subsequently commenced palliative chemotherapy with gemcitabine and nab-paclitaxel, which was ceased after two months when he developed symptomatic progression confirmed on a restaging CT scan. Sadly the patient died seven months after his initial presentation with visceral metastatic disease. Vemurafenib is a tyrosine kinase inhibitor of certain mutated forms of BRAF, which has been demonstrated to offer a survival benefit in patients with metastatic melanoma, who possess characteristic V600 (glutamic acid substituted for valine at amino acid 600) BRAF mutations.1,2 BRAF mutations have been identified in approximately 40–70% of melanomas,3 with V600E being overwhelmingly the most common mutation.4 This case is noteworthy because it raises the concern that vemurafenib, while inducing regression of the patient’s metastatic melanoma, simultaneously promoted the rapid growth of a pre-existing primary pancreatic adenocarcinoma. One of the well-documented toxicities of vemurafenib is the increased risk of non-melanoma cutaneous malignancies, namely squamous cell carcinomas (SCC) 598
and keratoacanthomas.1,5 A putative mechanism for development of these malignancies relates to the presence of activating RAS mutations in BRAF wild-type keratinocytes. BRAF plays a role in the MAP kinase pathway, a signalling cascade that influences cell proliferation.4,6 In contrast to their inhibitory effects on cell proliferation in BRAF-mutant cells, BRAF inhibitors, including vemurafenib, have been demonstrated to enhance ERK signalling in wild-type BRAF cells, thereby encouraging cell proliferation, in a manner which is dependent on RAS activity.7,8 There is some evidence that RAS mutations are present at an increased frequency in cutaneous SCC and keratoacanthomas among patients receiving vemurafenib in comparison with spontaneously occurring SCC, with HRAS mutations being most commonly identified.9–11 Further evidence to support this hypothesis relates to the observation that the incidence of non-melanoma cutaneous malignancies appears to be lower when BRAF inhibitors are combined with MEK1/2 inhibitors, which block downstream MAP kinase signalling.12 To the authors’ knowledge, there have been no previous published reports of solid organ, non-cutaneous malignancies arising or progressing as an adverse effect of vemurafenib treatment, although other authors have warned of this potential and pre-malignant lesions have been observed.13,14 In addition, this is the first known reported case of a KRAS-mutant solid malignancy progressing rapidly during vemurafenib therapy. The first published report of a non-cutaneous malignancy arising in conjunction with vemurafenib was a case of progression of chronic myelomonocytic leukaemia (CMML) in a patient receiving vemurafenib for metastatic melanoma.15 Analysis of bone marrow in that case revealed NRAS-mutant leukemic cell population. Peripheral blood mononuclear cells were sampled from the patient during vemurafenib treatment and 10 days after vemurafenib was ceased. Levels of phosphorylated ERK, in comparison with total ERK, were elevated in the vemurafenib sample when compared with the later sample, suggesting that vemurafenib treatment was promoting ERK activation amongst this subset of NRAS-mutant cells. There is a report of progression of KRAS-mutant colorectal cancer in a patient receiving combination therapy with the BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib,16 and solid organ, non-cutaneous malignancies (pancreas, glioblastoma, renal, colorectal) have been documented in 1% of patients receiving this same combination therapy.12 In addition, development of pre-malignant colonic and gastric polyps has been documented in association with vemurafenib therapy.17 In our case, the pancreatic adenocarcinoma appears to have been present prior to the introduction of treatment © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
Brief Communications
Figure 1 PET-CT at presentation: pancreatic mass and glucose uptake in right pelvic and iliac nodes.
with vemurafenib, given the presence of the 2.6-cm glucose avid lesion on the original PET-CT. The growth of the lesion following commencement of vemurafenib was rapid: it increased in size from 2.6 cm to 6 cm over the course of approximately 4 weeks. Figure 1 (original PETCT) and Figure 2 (subsequent PET-CT) illustrate the rapid evolution of the pancreatic mass, and the regression of the iliac and pelvic nodes. Just as RAS mutations have been identified as a potential culprit in the progression of cutaneous SCC during vemurafenib treatment, and in the case of CMML cited above, it is possible that a proproliferative interaction between BRAF inhibition and a pre-existing RAS mutation in the patient’s pancreatic adenocarcinoma explains the rapid expansion of the malignancy during treatment. RAS mutations, and in particular KRAS mutations, have been strongly implicated in the molecular biology of pancreatic adenocarcinoma.18 Activating KRAS mutations have been found to exist in 90% of non neuro-endocrine pancreatic malignancies.19 Molecular studies performed on a core biopsy of our
References 1 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larken J et al. Improved survival with vemurafenib in
Figure 2 Repeat PET-CT 2 weeks after commencement of vemurafenib: decreased glucose uptake in pelvic and iliac nodes but increased size of pancreatic mass.
patient’s adenocarcinoma revealed that it harboured a KRASQ61L mutation and was BRAF wild-type, supporting our hypothesis. BRAF inhibitors such as vemurafenib represent a significant advancement in the treatment of metastatic melanoma. Their use is likely to continue to increase, and their role may expand in the treatment of other types of malignancy. The possibility of an unwanted, proproliferative interaction between vemurafenib and preexisting RAS mutations raises the concern that we can expect to see further cases of progression of noncutaneous malignancies during vemurafenib treatment. This is particularly so given the high frequency of RAS mutations in human malignancies generally.20 The case highlights the need for clinicians to be vigilant to the possibility that treatment with BRAF inhibitors may promote growth of tumours other than cutaneous malignancies, and that this may occur very soon after commencement of therapy.
melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–16. 2 Chapman PB, Hauschild A, Robert C, Larken JMG, Haanen JB, Ribas A et al. Updated overall survival (OS) results for
© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-
599
Brief Communications
3
4
5
6
7
8
9
mutated melanoma. J Clin Oncol 2012; 30(Suppl): 8502. Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am 2009; 23: 529–45. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol 2010; 80: 561–7. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick A, Weber JS et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366: 707–14. Smalley KSM, Sondak VK. Melanoma – an unlikely poster child for personalised cancer therapy. N Engl J Med 2010; 363: 876–8. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464: 427–30. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464: 431–5. Oberholzer PA, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R et al. RAS mutations are associated with the
600
10
11
12
13
14
development of cutaneous squamous cell tumours in patients treated with RAF inhibitors. J Clin Oncol 2012; 30: 316–21. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366: 207–15. Uribe P, Gonzalez S. Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy. Pathol Res Pract 2011; 207: 337–42. Cebon J, Flaherty K, Weber J, Kim K, Infante J, Daud A et al. Comparison of BRAF inhibitor (BRAFi)-induced cutaneous squamous cell carcinoma (cuSCC) and secondary malignancies in BRAF mutation-positive metastatic melanoma patients treated with dabrafenib as monotherapy or in combination with MEK1/2 inhibitor (MEKi) trametinib [abstract]. JCO 2013 ASCO Annual Meeting Abstracts 2013; 31: 9016. Weeraratna AT. RAF around the edges – the paradox of BRAF inhibitors. N Engl J Med 2012; 366: 271–3. Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KS. Paradoxical oncogenesis – the long term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 2013; 10: 390–9.
15 Callaghan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T et al. Brief report: progression of RAS-mutant leukaemia during RAF inhibitor treatment. N Engl J Med 2012; 367: 2316–21. 16 Andrews M, Behren A, Chiohn F, Tebbutt N, Do H, Dobrovic A et al. Colorectal cancer promoted in a melanoma patient receiving dabrafenib (GSK2118436) in combination with MEK 1/2 inhibitor trametinib (GSK1120212) [abstract]. Pigment Cell Melanoma Res 2012; 25: 842. 17 Chapman P, Metz D, Sepulveda A, Uehara T, Rustgi A, Nathanson KL et al. Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib [abstract]. Pigment Cell Melanoma Res 2012; 25: 847. 18 Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–6. 19 Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM et al. High throughput oncogene mutation profiling in human cancer. Nat Genet 2007; 39: 347–51. 20 Karnoub AE, Weinberg RA. RAS oncogenes: split personalities. Nat Rev Mol Cell Biol 2008; 9: 517–31.
© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
Brief Communications
B R I E F C O M M U N I C AT I O N S
Progression of KRAS mutant pancreatic adenocarcinoma during vemurafenib treatment in a patient with metastatic melanoma A. Grey,1 A. Cooper,1 C. McNeil,1 S. O’Toole,2 J. Thompson1 and P. Grimison1 1
Sydney Cancer Centre and 2Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
Key words vemurafenib, BRAF inhibitor, melanoma, secondary malignancy, pancreatic adenocarcinoma. Correspondence Peter Grimison, Chris O’Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia. Email: [email protected]
Abstract Vemurafenib is a tyrosine kinase inhibitor of BRAF that prolongs survival in patients with BRAF V600-mutant metastatic melanoma. Secondary cutaneous malignancies are a well-documented toxicity of vemurafenib, thought to be mediated by enhanced ERK signalling in BRAF wild-type, RAS-mutant cells. Vemurafenib could also promote growth of non-cutaneous secondary malignancies by a similar mechanism. We present a case of an individual who received vemurafenib for metastatic melanoma and experienced rapid growth of a pre-existing KRAS-mutant pancreatic adenocarcinoma.
Received 2 October 2013; accepted 27 November 2013. doi:10.1111/imj.12415
A previously well 44-year–old man presented in 2006 with a primary cutaneous melanoma on his left neck, which was resected. Two years later, he developed stage M1a disease associated with multiple small intracutaneous metastases predominantly involving the scalp and neck. There was no evidence of visceral involvement on a staging computed tomography (CT) scan. Subsequent mutation testing on a resected intracutaneous metastasis revealed a BRAF V600E mutation. The patient’s cutaneous metastases were successfully treated with topical diphencyprone, and he subsequently went into complete remission. Six years after his initial diagnosis, the patient presented to hospital with several weeks of increasing epigastric pain, nausea, anorexia and weight loss. On examination, he was jaundiced. Liver function tests were deranged in an obstructive pattern. A CT scan of the abdomen revealed a 2.6-cm hypodense infiltrative mass
Funding: None. Conflict of interest: S. O’Toole reports personal fees from Pfizer Australia, Roche Australia and Lilly Oncology, and non-financial support from Roche, all outside the current article. J. Thompson reports personal fees from Provectus and GlaxoSmithKline, outside the current article. C. McNeil is a Roche Advisory Board Member (non-funded). © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
involving the pancreatic uncinate process with associated pancreatic and extrahepatic biliary dilatation. Positron emission tomography-CT (PET-CT) demonstrated uptake in the vicinity of the pancreatic uncinate process, as well as in porta hepatis, right pelvic and iliac lymph nodes. Given his previous diagnosis of stage M1a disease, this pattern on PET was felt most likely to represent metastatic melanoma. The patient underwent emergency therapeutic endoscopic retrograde cholangiopancreatography and biliary stenting of a distal common bile duct stricture. Post-procedure, the patient’s abdominal pain, jaundice and liver function tests improved. One week later, the patient was commenced on vemurafenib at a dose of 960 mg twice daily orally. This was later reduced to 720 mg twice daily when he developed a rash. Two weeks after starting vemurafenib, a repeat PET-CT scan revealed surprising, and mixed, results. There was decreased metabolism in the right pelvic, internal and common iliac nodes, suggestive of a response to vemurafenib. However, the pancreatic lesion was significantly larger, more necrotic and more glucose avid. This raised the suspicion of two separate malignancies: metastatic melanoma, which had responded to vemurafenib, and a primary pancreatic malignancy, which had rapidly progressed during vemurafenib treatment. Cytology from percutaneous fine needle aspiration 597
Brief Communications
of the pancreatic mass was consistent with a primary pancreatic adenocarcinoma. A restaging CT scan at 6 weeks after initial presentation to hospital showed a 6-cm locally advanced pancreatic cancer encasing the common bile duct and involving between 90 and 180 degrees of the superior mesenteric artery, and a new 7-mm hypodensity within segment eight of the liver that could represent a solitary metastasis, but which was not anatomically amenable to biopsy. In view of the rapid growth of the pancreatic adenocarcinoma, and the relatively indolent course of the metastatic melanoma, it was decided to proceed with concurrent chemoradiotherapy (using oral capecitabine) to the pancreas. The aims of treatment were to downstage the tumour, which could prevent local symptoms and prolong survival. Vemurafenib was ceased, given its unknown safety profile in combination with capecitabine-based chemoradiotherapy and because of concerns that the rapid growth of the pancreatic lesion may have been potentiated by vemurafenib therapy. Following completion of chemoradiotherapy, it was planned to restage both diseases and to consider further therapy directed at either the pancreatic cancer or melanoma. A restaging CT scan following 4 weeks of combined chemoradiotherapy revealed development of multiple hepatic lesions suspicious for metastases. Percutaneous liver biopsy demonstrated metastatic pancreatic adenocarcinoma rather than metastatic melanoma, which was positive for a KRASQ61L mutation. There was no evidence on follow-up CT scans to suggest progression of his metastatic melanoma within intra-abdominal or pelvic lymph nodes. The patient subsequently commenced palliative chemotherapy with gemcitabine and nab-paclitaxel, which was ceased after two months when he developed symptomatic progression confirmed on a restaging CT scan. Sadly the patient died seven months after his initial presentation with visceral metastatic disease. Vemurafenib is a tyrosine kinase inhibitor of certain mutated forms of BRAF, which has been demonstrated to offer a survival benefit in patients with metastatic melanoma, who possess characteristic V600 (glutamic acid substituted for valine at amino acid 600) BRAF mutations.1,2 BRAF mutations have been identified in approximately 40–70% of melanomas,3 with V600E being overwhelmingly the most common mutation.4 This case is noteworthy because it raises the concern that vemurafenib, while inducing regression of the patient’s metastatic melanoma, simultaneously promoted the rapid growth of a pre-existing primary pancreatic adenocarcinoma. One of the well-documented toxicities of vemurafenib is the increased risk of non-melanoma cutaneous malignancies, namely squamous cell carcinomas (SCC) 598
and keratoacanthomas.1,5 A putative mechanism for development of these malignancies relates to the presence of activating RAS mutations in BRAF wild-type keratinocytes. BRAF plays a role in the MAP kinase pathway, a signalling cascade that influences cell proliferation.4,6 In contrast to their inhibitory effects on cell proliferation in BRAF-mutant cells, BRAF inhibitors, including vemurafenib, have been demonstrated to enhance ERK signalling in wild-type BRAF cells, thereby encouraging cell proliferation, in a manner which is dependent on RAS activity.7,8 There is some evidence that RAS mutations are present at an increased frequency in cutaneous SCC and keratoacanthomas among patients receiving vemurafenib in comparison with spontaneously occurring SCC, with HRAS mutations being most commonly identified.9–11 Further evidence to support this hypothesis relates to the observation that the incidence of non-melanoma cutaneous malignancies appears to be lower when BRAF inhibitors are combined with MEK1/2 inhibitors, which block downstream MAP kinase signalling.12 To the authors’ knowledge, there have been no previous published reports of solid organ, non-cutaneous malignancies arising or progressing as an adverse effect of vemurafenib treatment, although other authors have warned of this potential and pre-malignant lesions have been observed.13,14 In addition, this is the first known reported case of a KRAS-mutant solid malignancy progressing rapidly during vemurafenib therapy. The first published report of a non-cutaneous malignancy arising in conjunction with vemurafenib was a case of progression of chronic myelomonocytic leukaemia (CMML) in a patient receiving vemurafenib for metastatic melanoma.15 Analysis of bone marrow in that case revealed NRAS-mutant leukemic cell population. Peripheral blood mononuclear cells were sampled from the patient during vemurafenib treatment and 10 days after vemurafenib was ceased. Levels of phosphorylated ERK, in comparison with total ERK, were elevated in the vemurafenib sample when compared with the later sample, suggesting that vemurafenib treatment was promoting ERK activation amongst this subset of NRAS-mutant cells. There is a report of progression of KRAS-mutant colorectal cancer in a patient receiving combination therapy with the BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib,16 and solid organ, non-cutaneous malignancies (pancreas, glioblastoma, renal, colorectal) have been documented in 1% of patients receiving this same combination therapy.12 In addition, development of pre-malignant colonic and gastric polyps has been documented in association with vemurafenib therapy.17 In our case, the pancreatic adenocarcinoma appears to have been present prior to the introduction of treatment © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
Brief Communications
Figure 1 PET-CT at presentation: pancreatic mass and glucose uptake in right pelvic and iliac nodes.
with vemurafenib, given the presence of the 2.6-cm glucose avid lesion on the original PET-CT. The growth of the lesion following commencement of vemurafenib was rapid: it increased in size from 2.6 cm to 6 cm over the course of approximately 4 weeks. Figure 1 (original PETCT) and Figure 2 (subsequent PET-CT) illustrate the rapid evolution of the pancreatic mass, and the regression of the iliac and pelvic nodes. Just as RAS mutations have been identified as a potential culprit in the progression of cutaneous SCC during vemurafenib treatment, and in the case of CMML cited above, it is possible that a proproliferative interaction between BRAF inhibition and a pre-existing RAS mutation in the patient’s pancreatic adenocarcinoma explains the rapid expansion of the malignancy during treatment. RAS mutations, and in particular KRAS mutations, have been strongly implicated in the molecular biology of pancreatic adenocarcinoma.18 Activating KRAS mutations have been found to exist in 90% of non neuro-endocrine pancreatic malignancies.19 Molecular studies performed on a core biopsy of our
References 1 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larken J et al. Improved survival with vemurafenib in
Figure 2 Repeat PET-CT 2 weeks after commencement of vemurafenib: decreased glucose uptake in pelvic and iliac nodes but increased size of pancreatic mass.
patient’s adenocarcinoma revealed that it harboured a KRASQ61L mutation and was BRAF wild-type, supporting our hypothesis. BRAF inhibitors such as vemurafenib represent a significant advancement in the treatment of metastatic melanoma. Their use is likely to continue to increase, and their role may expand in the treatment of other types of malignancy. The possibility of an unwanted, proproliferative interaction between vemurafenib and preexisting RAS mutations raises the concern that we can expect to see further cases of progression of noncutaneous malignancies during vemurafenib treatment. This is particularly so given the high frequency of RAS mutations in human malignancies generally.20 The case highlights the need for clinicians to be vigilant to the possibility that treatment with BRAF inhibitors may promote growth of tumours other than cutaneous malignancies, and that this may occur very soon after commencement of therapy.
melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–16. 2 Chapman PB, Hauschild A, Robert C, Larken JMG, Haanen JB, Ribas A et al. Updated overall survival (OS) results for
© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-
599
Brief Communications
3
4
5
6
7
8
9
mutated melanoma. J Clin Oncol 2012; 30(Suppl): 8502. Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am 2009; 23: 529–45. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol 2010; 80: 561–7. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick A, Weber JS et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366: 707–14. Smalley KSM, Sondak VK. Melanoma – an unlikely poster child for personalised cancer therapy. N Engl J Med 2010; 363: 876–8. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464: 427–30. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464: 431–5. Oberholzer PA, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R et al. RAS mutations are associated with the
600
10
11
12
13
14
development of cutaneous squamous cell tumours in patients treated with RAF inhibitors. J Clin Oncol 2012; 30: 316–21. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366: 207–15. Uribe P, Gonzalez S. Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy. Pathol Res Pract 2011; 207: 337–42. Cebon J, Flaherty K, Weber J, Kim K, Infante J, Daud A et al. Comparison of BRAF inhibitor (BRAFi)-induced cutaneous squamous cell carcinoma (cuSCC) and secondary malignancies in BRAF mutation-positive metastatic melanoma patients treated with dabrafenib as monotherapy or in combination with MEK1/2 inhibitor (MEKi) trametinib [abstract]. JCO 2013 ASCO Annual Meeting Abstracts 2013; 31: 9016. Weeraratna AT. RAF around the edges – the paradox of BRAF inhibitors. N Engl J Med 2012; 366: 271–3. Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KS. Paradoxical oncogenesis – the long term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 2013; 10: 390–9.
15 Callaghan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T et al. Brief report: progression of RAS-mutant leukaemia during RAF inhibitor treatment. N Engl J Med 2012; 367: 2316–21. 16 Andrews M, Behren A, Chiohn F, Tebbutt N, Do H, Dobrovic A et al. Colorectal cancer promoted in a melanoma patient receiving dabrafenib (GSK2118436) in combination with MEK 1/2 inhibitor trametinib (GSK1120212) [abstract]. Pigment Cell Melanoma Res 2012; 25: 842. 17 Chapman P, Metz D, Sepulveda A, Uehara T, Rustgi A, Nathanson KL et al. Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib [abstract]. Pigment Cell Melanoma Res 2012; 25: 847. 18 Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–6. 19 Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM et al. High throughput oncogene mutation profiling in human cancer. Nat Genet 2007; 39: 347–51. 20 Karnoub AE, Weinberg RA. RAS oncogenes: split personalities. Nat Rev Mol Cell Biol 2008; 9: 517–31.
© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians
