Esophageal cancer and drugs

 

Background in esophagus cancer Over 400 000 people are diagnosed annually with this cancer (WHO figures) and it is rising in incidence, one of the few cancers showing a rising trend over the past 30 years. About 17 000 cases will be diagnosed in the US in 2015 and 15 600 mortalities (Seer estimates). Squamous Cell Carcinoma (SCC) is most common and incidence in the US has been declining (probably due to reduced alcohol and tobacco use). The incidence of adenocarcinoma (located lower down, nearer to the stomach) is rising, for instance in the US and England. In this case H Pylori is declining and is thought to be protective for adenocarcinoma. Prognosis The 5-year relative survival rate for patients with esophageal cancer is 39% for patients with localized disease; 21% for regional disease; and 4% for metastatic disease (source: cancer research.org). The overall 5-year relative survival for 2002-2008 from 18 SEER geographic areas was c17%. The 5-year survival in the US is around 18% and in Europe around 11%. Survival has improved, since in the 1960's and 1970's 5-year survival was around 5%. The 5-yr survival stats can be as high as 40% if the cancer is only local. If it is regional (has spread to lymph nodes nearby or other tissues) then the 5-yr survival rates may be 20%. If it is distant (lymph nodes, but also organs away from the tumour) then 5-yr survival rates are only 4%. In the approximately 30% of cases that come from HPV, prognosis is better (see below.

 

Causes

 

Tobacco and Alcohol consumption are the 2 primary causes that we know of today. Nutritional deficiency is a suggested cause due to high prevalence in China and beyond, but it appears for cancer to occur, a carcinogen also needs to be present. Hot Beverages where there is frequent consumption, appears to increase SCC incidence. Food retention may also be a risk since retained food needs bacteria to decompose and these bacteria may release chemical irritants. Obesity appears to be correlated with esophageal adenocarcinoma incidence. Overweight people have up to 3 times the risk. Rather than assuming obesity leads to esophageal cancer, consider that the same thing may cause obesity and esophageal cancer.

 

HPV, especially HPV-16 and HPV -18, causes about 30% of esophageal, but having HPV antibodies also comes with a better prognosis. We can check for HPV antibodies. According to a University of Oxford study 35% of a sample with throat cancer had HPV antibodies, whilst 1% without throat cancer had the antibodies. There were 84% of people with the antibodies alive 5 years after diagnosis compared to 58% of people alive after 5 years without the antibodies (where other causes were involved such as tobacco/alcohol). According to this study there are antibodies to a key HPV protein called E6. E6 knocks out part of the cell protection system, which normally should prevent cancer. We can also now take a vaccine for HPV to prevent esophageal cancer risk. The vaccine prevents the virus getting into cells and damaging them. A certain gene predisposes to esophageal cancer, which also relates to a rare skin condition of the skin and mouth called tylosis. The exact gene on the chromosome is now found.

 

Standard of care is surgery, chemotherapy and radiation. Minimally invasive procedures may be as effective as surgery, since lung infection often occurs with surgery. Surgery is often performed to deal with side effects such as obstruction, and reconstruction of the esophagus from a graft in addition to the cancer itself. Treating gastric reflux with proton pump inhibitor drugs (Prilosec, Prevacid, Nexium), or through surgery may be able to prevent Barrett’s esophagus and esophageal cancer (source: cancer.org).

 

New biomarkers try to understand which patients may or may not respond to treatments (such as chemotherapy, surgery or immunotherapy). For instance patients with higher than normal fibroblast growth factor receptor-2 (FGFR2) levels tend to respond poorly to standard treatment approaches such as chemotherapy. FGFR signals cell growth and survival and may be faulty in cancer cells, which continue to divide. See colorectal.

 

Some potential new treatments - see table. This is the text version

 

Targeted therapies to address specific gene variants may emerge as we understand which gene variants are more prevalent. For instance in Barrett's esophagus, targeted therapy may include trastuzumab (Herceptin), which interferes with the protein on esophageal cancer cells called HER2. HER2 helps cancer cells grow and spread. Only a small portion of esophagus cancers (mostly adenocarcinomas) have too much of this HER2 protein, but this drug may be able to help treat these cancers in future (source: cancer.org).

 

GDC-006 by Genentech/Roche is an Akt inhibitor (part of the Pi3k pathway) being evaluated with Folfox chemotherapy in a Phase 2 gastric or gastroesophageal junction cancer study.

 

Immunotherapies in esophagus cancer

 

Keytruda by Merck, showed a 30-40% objective response rate, with tumour shrinkage in 52% of patients in 23 heavily pre-treated patients with advanced esophageal cancer at the annual meeting of the American society of clinical oncology (ASCO) in Chicago, May 29 – June 2, 2015

 

Opdivo by BMS and ONO who have a Phase 2 trial for advanced esophageal cancer

 

MEDI4736 by Astrazeneca a phase 1/ 2 for patients with advanced solid tumours Earlier Phase 1 studies and combination studies with immunotherapy drugs for esophagus cancer:

 

Urelumab by BMS have a Phase 1 for advanced cancers. This drug is an anti-4-1BB (CD137)Lirilumab (anti-KIR antibody; BMS) in combination with Nivolumab in a Phase 1 study in patients with advanced solid tumours

 

Ipilimumab (Yervoy®), an anti-CTLA-4 antibody, plus Gleevec a c-Kit inhibitor, in a Phase 1 study for patients with advanced cancer

 

BMS-986016 (an anti-LAG-3 antibody) with or without nivolumab (Opdivo®), in a Phase 1 combination study for patients with solid tumours

 

PF-05082566 by Pfizer is an anti-4-1BB/CD137 antibody that is being tested in a phase I trial for patients with solid tumours

 

MPDL3280A by Genentech/Roche is in a Phase 1 trial for numerous cancers. There is also a trial with MPDL plus Avastin for advanced cancers

 

MSB0010718C, by EMD Serono, an anti-PD-L1 antibody, is in a combination phase 1 study of solid tumours, including oesophageal cancer

 

Mogamulizumab (Poteligeo®, KW-0761) by Kyowa Hakko Kirin is an anti-CCR4 antibody in a phase I trial for patients with advanced solid tumours BMS announced a collaboration with this company on 29th July 2015 to conduct Phase 1/ 2 trials in metastatic solid tumours with Opdivo. Dicerna also have a partnership with this company.End of document