As part of a four part series on personalized therapy for lung cancer, here is the second summary in the series based on some fascinating lectures at the AACR meeting on the molecular origins in lung cancer this week.
The second presentation I really enjoyed on biomarkers and personalized therapy looked at the ‘blind alley’ that
many are still using to distinguish patients. Histology, as Dr David Gandara aptly
described it, is a rather ‘crude form of molecular selection’ that is likely to
be a transient one. He provided a
telling example of two patients with a different case history:
- 65 yo
male who smokes, has a squamous histology, KRAS mutation, low ERCC1 and low
- 39 yo
female who is a non-smoker with a adenocarcinoma, EGFR mutation and high ERCC1
and high RRM1
He then posed the question to the audience of whether it is still
appropriate to treat these two patients the same way?
What was abundantly clear at this meeting to me is that the
answer would be an emphatic ‘no’ based, not on their physical characteristics
and histology, but on the underlying biology. Whether that is a view held by the majority of community
oncologists, I’m not so sure though.
Excision repair cross-complementing gene (ERCC1) is an interesting biomarker that was first mooted nearly ten years ago and has received little attention, but is now coming back to the fore as clinical trials and modeling techniques catch up with basic biology. It encodes a nucleotide excision repair protein that repairs a range of lesions, including UV-induced thymine dimers and other photoproducts, and also lesions caused by a variety of chemical agents including the platinums.
Dr Gandara noted that low
levels are prognostic in early stage I/II NSCLC and predictive of a
poor response in metastatic disease, thus suggesting that platinum chemotherapy
would be optimal, e.g using a gemcitabine-cisplatin combination, whereas early
stage patients with high levels of ERCC1 would have a good prognosis and likely
do better without chemotherapy. ERCC1 has also been shown to play a role in DNA repair after cisplatin damage. Interestingly, high tumour tissue levels of ERCC1 mRNA in ovarian and gastric cancer patients have been associated with cisplatin resistance.
Similarly, RRM1 is useful for predicting response to
gemcitabine and TS for pemetrexed. Although pemetrexed is approved for use in treating non-squamous
patients, what about TS expression in lung cancer? Gandara noted the general trend towards high TS in SCLC and
squamous cell carcinoma and low TS in patients with adenocarcinoma. Knowing this kind of information about
the tumour biology (ERCC1, RRM1
and TS) can therefore be potentially useful in deciding which chemotherapy
regimen to use.
What this AACR meeting really brought to the fore to me is
the gradual move from rather crude methods to more sophisticated ways of
defining patient subsets as our knowledge and understanding of biology
Sometimes though, the
gap between published research and clinical trials also lags, mainly because of
either the cost of tumour biopsy and biomarker studies in large scale trials or
the development of new inhibitors designed to target the molecular abnormality
identified. The impression I came
away with is that the next five years may well produce some really big advances in
both basic science and clinical practices that will contribute to a more logical and scientific approach to the treatment of a hard to treat cancer.
Times are a-changin’ and that’s great news for patients with
Dabholkar, M., Vionnet, J., Bostick-Bruton, F., Yu, J., & Reed, E. (1994). Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. Journal of Clinical Investigation, 94 (2), 703-708 DOI: 10.1172/JCI117388
Cobo, M., Isla, D., Massuti, B., Montes, A., Sanchez, J., Provencio, M., Vinolas, N., Paz-Ares, L., Lopez-Vivanco, G., Munoz, M., Felip, E., Alberola, V., Camps, C., Domine, M., Sanchez, J., Sanchez-Ronco, M., Danenberg, K., Taron, M., Gandara, D., & Rosell, R. (2007). Customizing Cisplatin Based on Quantitative Excision Repair Cross-Complementing 1 mRNA Expression: A Phase III Trial in Non-Small-Cell Lung Cancer Journal of Clinical Oncology, 25 (19), 2747-2754 DOI: 10.1200/JCO.2006.09.7915