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The new paradigm of genetic targeting in cancer treatment

The emergence of targeted therapies for cancer has been one of the most profound changes in the oncolology field in recent years. Dr Mark Kris, Consultant Oncologist at the Memorial Sloan Kettering Cancer Centre, US, a pioneer in the field who has played a leading role in researching these new agents, spoke at the ISMO 2016 Fellowship and Bursary Awards meeting, which took place in the Mater Hospital, Dublin, on February 6, on the subject of uncovering oncogenic drivers to choose targeted therapies for lung cancers.

Dr Kris, in his work with the Lung Cancer Mutation Consortium (LCMC), was involved in a major study from 2009 through 2012, in which 14 sites in the US enrolled patients with metastatic lung adenocarcinomas and tested their tumours for 10 drivers. Tumours from 1,007 patients were tested for at least one gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64 per cent). Among these 733 tumours, 182 tumours (25 per cent) had the KRAS driver; sensitising EGFR, 122 (17 per cent); and ALK rearrangements, 57 (8 per cent).

Results were used to select a targeted therapy or trial in 275 of 1,007 patients (28 per cent). The median survival was 3.5 years for the 260 patients with an oncogenic driver and genotype-directed therapy, compared with 2.4 years for the 318 patients with any oncogenic drivers who did not receive genotype-directed therapy.

New therapies

The discovery of the role of EGFR mutations in lung cancer, in which Dr Kris and his colleagues played a leading part, has led to the development of novel therapies that target specific genetic material and offer a personalised approach to treatment. EGFR belongs to the ErbB family of receptor tyrosine kinases (RTK). These trans-membrane proteins are activated following binding with peptide growth factors of the EGF family of proteins.

Dr Kris outlined how tyrosine kinase inhibitors (TKIs) — such as erlotinib, afatinib and gefitinib — can be used alone without chemotherapy as the first treatment for advanced non-small cell lung cancer (NSCLC) that have certain mutations in the EGFR gene. Research has shown that treatment with erlotinib leads to a 16-month median progression-free survival, and that the median survival from the time of metastatic disease of patients with EGFR mutations is four years. He told the meeting that identifying the differences in efficacy between these agents can prove challenging.

‘Personalised care for lung cancer is here,’ Dr Kris concluded. ‘More choices require more decisions and lead to better outcomes’

Recent data from the LUX-Lung 7 trials compared afatinib and gefitinib. According to the results, the response rate of afatinib was 70 per cent, compared with 56 per cent for gefitinib. The median response duration was 10 months for afatinib, compared with eight months for gefitinib. The trial showed 18 per cent of afatinib patients were progression-free after 24 months, compared to 8 per cent of gefitinib patients, while the median time to treatment failure was 14 months compared with 12 months. There was no difference in median progression-free survival (both 11 months) and overall survival was not reported.

Dr Kris also cited a Japanese study from 2014 examining the potential for erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous, non-small-cell lung cancer harbouring EGFR mutations. For the study, 77 patients were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16 months with erlotinib plus bevacizumab and 9.7 months with erlotinib alone. The study found that the erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC.

Dr Kris also praised US regulatory authorities for the speed at which agents such as crizotinib have been approved, and for how the new agents are incorporated into guidelines in a short space of time.

The biology of mutations and resistance is incredibly complex, according to Dr Kris.

Mutations

He said it was important to remember differences in EGFR mutations should be taken in account, with particular regard to resistance to therapy. For example, in contrast to other primary EGFR mutations, the majority of patients with advanced lung adenocarcinomas harbouring EGFR exon 20 insertion do not respond to EGFR TKI therapy. Deciding when to continue or cease TKI therapy in the face of resistance can be difficult, he said. Note should be taken of whether there is a secondary mutation that is affecting treatment.

Next-generation testing offers great benefits in providing detailed genetic information that will impact future treatment options, Dr Kris said, citing a study regarding patients with no EGFR mutation that had a dramatic response to afatinib. While traditional genetic testing found no mutation, next-generation testing found the reason why these patients responded to therapy was the presence of EGFR kinase domain duplication.

New era

Summarising, Dr Kris said the “carbotaxol for all” treatment era of lung cancers is over. Advances in cancer biology have changed care, with approaches targeting drivers “biologically based and patient-specific”. Precise pathologic diagnoses are a must and multiplexed testing should be done at diagnosis. In cases where no targeted therapy is available or no target has been detected, chemotherapy should be used. It has also been shown that chemotherapy works better for cancers with genetic drivers, he noted. Targeted therapies are standard for patients with stage IV lung cancer, while results justify local therapies in stages I-III.

“Personalised care for lung cancer is here,” Dr Kris concluded. “More choices require more decisions and lead to better outcomes.”

Bursary Award Winners

As for the Bursary Awards themselves, a total of 14 winners were announced at the end of the meeting. They were: Dr Jack Gleeson, Mater Hospital; Dr Geoff Watson, Mater Hospital; Dr Deaglan McHugh, St James’s Hospital, Dublin; Dr Lisa Prior,  Mater Hospital; Dr Scheryll Alken, University Hospital Limerick; Dr Fergus Keane, Galway University Hospital; Dr Emily Harrold,  Mater Hospital; Dr Leah Halpenny, Beaumont Hospital, Dublin; Dr Deirdre Kelly, Mater Hospital; Dr Marvin Lim, Mater Hospital; Dr Michael McCarthy, University Hospital Limerick; Dr Dearbhla Murphy, Mater Hospital; Dr Niamh Keegan, Beaumont Hospital; and Dr Tomás Lyons, Cork University Hospital.

Immune checkpoint inhibitor

Dr Gleeson’s paper examined whether immune checkpoint inhibitor induced thyroid dysfunction impacts on side-effect profile.

The immune checkpoint inhibitor medications have the reported class effects of inducing hypo- or hyperthyroidism in a small but significant number of patients.

However, the reported rates of these vary by study. Anecdotally, a correlation has been seen between thyroid dysfunction and adverse side-effect profile.

All patients who received one or more of the immune checkpoint inhibitors were found on the computer-based prescribing system, CATO, and their charts were reviewed retrospectively. Patients on active clinical trials were excluded due to data rights issues.

A total of 18 patients received a total of 21 drugs comprising 106 treatment cycles. Thyroid dysfunction was seen in 16.6 per cent (3/18) of patients, all of which involved hypothyroidism. No hyperthyroidism was seen.

A positive correlation was seen between thyroid dysfunction and increasing numbers of side-effects, however this was not statistically significant.

Dr Gleeson concluded that immune checkpoint inhibitors in the reviewed cases caused thyroid dysfunction at rates higher than those reported in the literature. Thyroid dysfunction is associated with a higher rate of all-grade side-effects in these patients. This pilot study supports the hypothesis that that immune checkpoint inhibitor-induced thyroid dysfunction impacts the side-effect profile of patients on these therapies.

Double hit

Dr McHugh examined the prevalence, clinico-pathological features and outcomes of ‘double-hit’ high-grade B-cell non-hodgkins lymphoma. MYC/BCL2 (or MYC/BCL6) double-hit lymphoma (DHL) is defined as a large B-cell lymphoma with concurrent translocations. Several studies indicate that up to 10 per cent of diffuse large B-cell lymphomas (DLBCLs) harbouring a MYC rearrangement portends a poorer prognosis, worse still when present with a BLC2/6 rearrangement. Currently, there is a relative paucity of guidelines on bridging together data to decide the most effective therapy in patients with DHL.

Moreover, the prognostic implications of a high MYC, BCL2 or BCL6 protein expression without a concomitant translocation remains poorly defined. For the study, from August 2013 to October 2015 inclusive, all patients with high-grade large B-cell lymphoma who had tissue samples referred to the central pathology laboratory at St James’s Hospital, Dublin, were included for analysis. Patient demographics, clinical features (stage at diagnosis, bone marrow and/or extranodal involvement, international prognostic index), histopathological details, systemic therapy received and patient-related outcomes (treatment response, consolidation therapy if any, relapses or death if any and last follow-up) were recorded from electronic or paper medical records.

Wilms’ tumour is one of the most common malignancies in childhood, accounting for seven of paediatric malignancies, but it is significantly rarer in adulthood

All cases were reviewed by a consultant histopathologist. MYC and BCL2 rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual colour fusion probes. A total of 152 cases of high-grade B-cell NHL were identified since FISH testing for MYC rearrangement commenced in St James’s Hospital, including (based on World Health Organisation 2008 classification) all DLBCL, Burkitts lymphoma (BL) and B-cell lymphoma unclassifiable-intermediate between DLBCL and BL (BCLU).

A total of 16 cases of showed MYC rearrangement by FISH. Of these cases, 11 patients also had a BCL2 rearrangement present. One patient with MYC and BCL2 rearrangements also had a BCL6 rearrangement. The median age of the MYC/BLC2 rearranged patients was 54 years (range 39 to 73), with 64 per cent of patients female. Patients were treated with varying regimens, including R-CHOP or R-CHOP-like chemo-immunotherapy, autologous or allogeneic stem cell transplantation.

In the study of all high-grade NHL, 11 per cent showed a MYC rearrangement. The frequency of double-hit lymphoma was 7 per cent.

There was considerable heterogeneity with regard to systemic therapies received and clinical outcomes.

Immunotherapies

Dr Prior, whose paper was subtitled ‘traversing unknown territories’, examined the toxicities of immunotherapy. Immunotherapy, including CTLA-4 and PD-1 receptor antibodies, has been shown to improve survival outcomes in patients with metastatic malignant melanoma. Its role also looks promising in the treatment of other malignancies in the future.

Despite these revolutionary advances however, the use of checkpoint inhibitors is associated with a unique spectrum of immune-related toxicities that are distinct to those encountered with conventional cytotoxic chemotherapy. These toxicities are significant and can lead to interruption or discontinuation of therapy, thus affecting their efficacy.

Dr Prior’s research presented an academic cancer centre’s experience to date of adverse events related to immunotherapy. For the study, all patients who were identified from pharmacy records on the Mater campus that were treated with immunotherapy since its introduction were reviewed. These patients included those who had been treated on a clinical trial (unblinded patients only), expanded access programme and on a compassionate use basis.

It was found that in congruence with existing literature on checkpoint inhibitors, toxicities frequently encountered included dermatological, gastrointestinal and endocrine adverse effects.

A number of patients experienced distinct immune-related side-effects not previously explored in the literature before, including oral erythema multiforme, orbital myositis and scleroderma.

These rarer side-effects were further illustrated with the case of a 67-year-old woman with stage IV malignant melanoma who developed grade 3 oral mucositis on a PD-1 inhibitor.

A biopsy of the oral lesions confirmed erythema multiforme.

Immunotherapy was subsequently withdrawn and steroids were commenced to mitigate the immune response from therapy. This resulted in resolution of mucositis. Steroids were slowly tapered over a number of weeks. On cessation of immunosuppression, she suffered relapse of mucositis, in addition to peripheral erythema multiforme.

This case demonstrates the prolonged interaction of immunotherapy with the host environment, despite discontinuation of therapy.

Long-term trastuzumab treatment

Dr Keane’s paper examined long-term trastuzumab treatment. The incorporation of the monoclonal antibody trastuzumab into the treatment paradigm for HER2-positive metastatic breast cancer has revolutionised the disease and improved both progression-free and overall survival in this patient cohort.

However, as with many targeted agents, long-term treatment with trastuzumab is associated with a number of adverse effects, most notably cardiotoxicity.

In patients with metastatic disease, who achieve a complete clinical and radiological response to therapy, there remains uncertainty regarding the optimal length of trastuzumab treatment. This is largely due to a lack of randomised controlled trials in this setting.

The study consisted of a retrospective review of patients with a diagnosis of metastatic breast cancer who had been treated with long-term trastuzumab treatment at Galway University Hospital. Patients with a diagnosis of metastatic breast cancer who have received trastuzumab for more than three years and who experienced a complete response to treatment were identified from clinical and pharmacy databases. An extensive review of electronic patient records was carried out. Patient demographics, response duration and survival data were assessed.

A total of seven patients with a diagnosis of metastatic breast cancer who had received trastuzumab for more than three years and had a complete response to treatment were identified. The median age at diagnosis was 48.5 years (range 22 to 54 years). The median duration of trastuzumab treatment in this subgroup was 79 months (range 40-131 months). The median duration of complete response among this group of patients was 68 months (range 23 to 145 months). To date, each patient remains on trastuzumab, despite the absence of measurable disease.

It was concluded that further studies are required regarding the optimal duration of treatment in patients who have shown complete response to trastuzumab.

Wilms’ tumours

Dr Halpenny examined managing a children’s cancer in the adult setting.

In the presented case, a 21-year-old female presented with a two-year history of flank pain, which was initially intermittent but later became constant. In the two months prior to presentation, she reported a loss of appetite, one stone weight loss and constipation.

On examination, there was right-sided abdominal tenderness and guarding, with a palpable right-sided abdominal mass. CT scan revealed a large, heterogenous right kidney mass, associated regional lymphadenopathy, and multiple pulmonary nodules, consistent with metastatic renal cell carcinoma. A lung biopsy showed poorly-differentiated tumour composed of small cells, with hyperchromatic round and focally angulated nuclei. Renal biopsy revealed a small, round blue-cell malignant tumour with focal tubular and blastematous areas, with strongly positive immunostaining for Wilms’ tumour 1 (WT1). A second pathology opinion suggested the most likely diagnosis was metastatic Wilms’ tumour.

The patient received primary chemotherapy with doxorubicin, daptomycin and vincristine for six cycles. She had an excellent clinical response and a CT scan showed near complete resolution of pulmonary disease and a dramatic reduction in the size of the primary tumour.

Nephrectomy was performed, which showed a relatively poor treatment response, with only 10 per cent necrosis of the primary tumour. Following recovery from surgery, a restaging CT showed substantial progression of pulmonary metastases. She then commenced second-line carboplatin-based chemotherapy. This treatment is ongoing and an interim CT has showed improvement in her disease.

Wilms’ tumour is one of the most common malignancies in childhood, accounting for seven of paediatric malignancies, but it is significantly rarer in adulthood as only 3 per cent of Wilms’ tumours occur in adults. Although paediatric Wilms’ tumour has almost 90 per cent survival, outcomes are poorer in adults. As this is a relatively rare cancer, there is a lack of prospective research to guide therapy for adults and treatment is generally extrapolated from the paediatric oncology setting.

In paediatric Wilms’, the genetic alterations (including WTX, WT1 and CTNNB1 mutations) are well documented, and it appears adult Wilms’ tumour might have a unique genetic makeup. In summary, Dr Halpenny said this case highlights a significant diagnostic and therapeutic challenge in the adult oncology setting, and highlights the importance of collaboration and discussion between paediatric and adult oncology colleagues.

Metastatic medullary thyroid carcinoma

Dr Kelly’s study presented a molecular analysis of a novel case of metastatic medullary thyroid carcinoma and reviewed the recent developments in targeted therapy.

A 36-year-old man presented with disseminated intravascular coagulation and respiratory distress. Subsequent investigations including a bone marrow test were consistent with metastatic medullary thyroid cancer. He received treatment with sorafenib and vandetanib. Unfortunately, his disease was rapidly progressive and he passed away from multi-organ failure. Molecular analysis was undertaken.

A systematic literature review of journal articles published between December 2009 and December 2015 was performed for studies conducted in Europe and the US using Medline and Pubmed. Seven studies were included with a total of 698 patients with advanced medullary thyroid cancer.

Vandatanib was associated with a 16 per cent overall response rate. Sorafenib had a 17.9 month progression free survival. Cabozantanib demonstrated a 68 per cent partial response and pazopanib had a 14.3 per cent partial response.

The genetic analysis of the case study man revealed a non-synonymous missense mutation in CDKN2C on chromosome 1 exclusive to the primary tumour. There was loss of heterozygosity in six genes; ALK, ATM, CSF1R, GNAS, SMARCB1, NOTCH1. There was a chromothripsis-like event identified on chromosome 4.

 In conclusion, Dr Kelly stated that this is the first recorded case of medullary thyroid cancer presenting with diffuse bone marrow involvement causing disseminated intravascular coagulation.

It presented significant diagnostic and clinical challenges. It may represent a unique subset of this disease. Two findings with potential therapeutic implications were identified — a missense mutation in CDKN2C and a chromothripsis-like event on chromosome 4. The results support current recommendations to initiate TKI therapy in the first-line setting for advanced unrespectable medullary thyroid cancer.

VEGF-TKI induced hypertension

Dr Lim’s study sought to evaluate the current antihypertensive choice for VEGF-TKI induced hypertension and to set up a protocol for first-line management of VEGF-TKI induced hypertension in this cohort.

The medical records of 13 patients with metastatic renal cell carcinoma who attended the oral therapy clinic between January 2014 and June 2015 were examined retrospectively. Data collected included age, gender, histology, types of VEGF-TKI treatments, baseline changes to blood pressure status post VEGF-TKI treatment and types of antihypertensive use. Antihypertensive agents were categorised to ASI (ACEI and ARB) and non-ASI.

Out of 13 patients, nine (69 per cent) were male and four (31 per cent) were female. A total of four out of 13 (31 per cent) patients had no baseline hypertension and the remaining nine (69 per cent) patients had baseline hypertension on antihypertensive.

All  four (100 per cent) of the non-hypertensive patients developed hypertension post VEGF-TKI treatment and non-ASI was prescribed as a first-line antihypertensive agent. A total of three out of nine (33 per cent) patients with baseline hypertension on antihypertensive agents did not develop poorly-controlled blood pressure post VEGF-TKI treatment, whereas the remaining six (67 per cent) patients did develop poorly controlled blood pressure requiring additional antihypertensive agents. A total of three out of the six (50 per cent) patients from the latter were already on an ASI agent and as for the remaining three (50 per cent) that were not on ASI agents, two were prescribed non-ASI and one was prescribed ASI.

The audit showed that the choices of antihypertensive agents used for VEGF-TKI induced hypertension are for the most part left to individual practitioner preference in this teaching hospital.

The standardising of first-line antihypertensive agents would result in enhancing quality of care for individual patients in terms of blood pressure management, while ensuring possible improved survival outcomes in the era of targeted therapy, the study concluded.

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