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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

ERCC1 in Early Stage NSCLC: Likely to Become an Important Marker in the Clinic
Sat, 11/17/2007 - 18:13
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Although I’ve described this concept in a few posts over the past year, it’s time for me to dedicate some real discussion to the concept of individualizing treatment with the ERCC1 marker. ERCC1 stands for excision repair cross-complementing group 1, and it helps repair damage to DNA. Now, validated, reliable testing for ERCC1 in tumor tissue isn’t commercially available yet to my knowledge; the company Oncotech, some of whose work I described in a prior post, has made this test available as part of their package, but I don't think it's validated, while other companies like Response Genetics and Genzyme are also working on a test for commercial use. The interesting thing is that ERCC1 at high levels is associated with more favorable survival after surgery and in the absence of cisplatin-based treatment. Why? Because a strong ability to repair DNA damage means that it’s possible to slow or reverse the mutation-induced problems caused by a cancer. But on the other hand, cisplatin fights cancer by inflicting damage against DNA, so expression of ERCC1 suggests that it’s easier to reverse the effects of cisplatin. And in the setting of treating patients with cisplatin-based chemo, ERCC1 expression is associated with worse survival. Looking at the results of a large post-operative chemo trial called IALT, in which half of the more than 1800 enrolled patients received adjuvant cisplatin-based chemo and half did not (abstract here), an analysis of tumor tissue from 761 patients from the IALT trial (abstract here) showed that in patients who had tumors with low ERCC1 expression by immunohistochemistry (and called ERCC1-negative, comprising 56% of those sampled), predicting a less favorable natural history (what would happen without treatment) but also an inability to repair cisplatin-induced damage, patients did significantly better with chemo vs. observation alone after surgery (median survival 56 vs. 42 months).

ERCC! IALT ERCC! neg

(Click on image to enlarge)

Conversely, in those positive for ERCC1 expression, who would be expected to be able to repair damage leading to development of future cancer but also a greater likelihood of being able to counteract cisplatin-induced DNA damage against a tumor, people receiving cisplatin-based chemo did worse. This was actually not a statistically significant difference, though) than patients who were just watched (50 vs. 55 months):

IALT ERCC! positive pts

Another report out of Korea (abstract here) confirmed that among 130 early stage NSCLC patients who did not receive adjuvant chemotherapy, ERCC1 expression was associated with a significantly longer survival than that seem among patients with ERCC1-negative cancers (90 vs. 47 months).

These findings for ERCC1 in early stage NSCLC are very interesting and somewhat problematic, because it’s not yet an available and approved test, but the results suggest that not only could using the test help refine our treatment plans, NOT using it could be associated with patients doing worse if they have ERCC1 positive cancers and receive chemo as a standard approach. The less favorable results on the IALT trial among patients with ERCC1-positive weren’t significantly worse, but perhaps these people really would do better either being observed or getting an alternative chemo strategy that doesn’t include cisplatin. We don't have any evidence either way on that idea.

For patients who are on the border for a recommendation to receive adjuvant cisplatin-based chemo, like those with stage IB cancers and older or marginal performance status patients who may not tolerate a post-operative cisplatin combination, having a test that can help us get off the fence and definitively recommend treatment or not would be very helpful. This testing might also help us identify people in a group, like stage I NSCLC, who might fall below the usual threshold for treating with chemo but who, with ERCC1-negative cancers, would be predicted to have a higher risk of recurrence and a greater sensitivity to cisplatin-based chemo. In fact, the Southwest Oncology Group is developing and close to activating a nationwide study like this that will submit tumor tissue for stage I (2 cm or larger) resected NSCLC tumor tissue to be tested for ERCC1, and then would treat those with ERCC1 negative cancers with cisplatin-based chemo but watch the others with ERCC1 positive cancers, who would be predicted to have lower risk and less benefit from cisplatin-based chemo.

This approach involves treating patients who would probably not be treated otherwise. But another potential scenario is that if I learn that someone with a stage II NSCLC had an ERCC1-positive tumor, this suggests that they will have a favorable natural history and be resistant to cisplatin-based chemo, but the standard of care is to treat with that chemo. Should we really recommend less treatment than would be considered "standard" for people based on this test that appears very helpful and promising but hasn't really been incorporated into clinical trials. Right now, many of us might be more inclined to recommend more treatment than standard on the basis of ERCC1 testing, or to modify our recommendations in a borderline case. But recommending less treatment than we'd otherwise seems more potentially problematic to me.

Fortunately, ERCC1 is a hot topic, and we'll keep getting more information and, I suspect, some validated tests for clinical testing soon (although I'm afraid not soon enough for many members to benefit from it).

All of this discussion of high ERCC1 expression being associated with better survival is in the setting of early stage NSCLC, not treated with chemo. But for advanced lung cancer, high expression of ERCC1 in advanced NSCLC generally translates to worse outcomes, at least among patients who receive platinum-based chemo, which is the current standard of care. I’ll discuss more on that issue next.

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