This is a bomb shell (forgive me if this is posted elsewhere) - 1262969

Big news this week, but it's important to note that this is still a rare cause of lung cancer. It means that if you have the genetic mutation, there is a nearly 1 in 3 chance of developing lung cancer over a lifetime (and I would argue therefore clearly appropriate to screen), but it isn't the underlying cause of lung cancer in the vast majority of people, or even in most never-smokers. I'm sure this will lead to much greater study to learn how prevalent it really is, but with 20,000-25,000 never-smokers each year in the US developing lung cancer, this rare mutation is only a very small piece of a much bigger puzzle of why some people develop lung cancer and others don't.

-Dr. West

1 in 3 chance of developing lung cancer over lifetime seems scary to me, but then again I think average lifetime change for developing lung cancer is 1 and 13.

As T790M is a resistant path for EGFR TKI's, does this mean that patients that are responding to EGFR TKI's are sure NOT having such inherited mutation?

Hi njliu,

Probably very likely, since you'd probably need to have the inherited mutation (rare enough in itself), be one of the two-thirds who don't develop lung cancer AND most likely develop a cancer driven by an EGFR TKI sensitive mutation. Not too likely.

JimC
Forum moderator

Greg Riely from Memorial Sloan-Kettering also reported at ASCO last year that the people with a de novo T790M mutation at the time of diagnosis (which is still most likely a random mutation in particular cells, not a "germline" mutation in all cells, the way an inherited mutation is) have a very low response rate to EGFR inhibitors like Tarceva (erlotinib). The response rate was under 10%, and the vast majority of the small cohort of patients progressed quite rapidly. The implication was that this is a very different patient population from the typical EGFR inhibitor population with an activating exon 19 or 21 EGFR mutation, and in those with a de novo EGFR mutation, it would be much more appropriate to start with a chemotherapy-based approach than to assume that you're going to get a major benefit from an oral EGFR inhibitor.

-Dr. West

I'm a bit confused by this post and the findings of this study. Does it mean that if my wife was EGFR positive my 2 daughters should at some point get tested? Bob

No, and I'll post on the significance of this study in the next day.

Basically, what it says is that the small minority of people about 1% of lung cancer patients, as alleged by the study) who have an inherited, germline T790M mutation in the EGFR gene, right from the time of diagnosis (it is more commonly developed later as a leading cause of acquired resistance to EGFR inhibitors, but that is a somatic (non-inherited/inheritable) mutation), which is associated with resistance to EGFR inhibitors, have a 31% chance of developing lung cancer over their lifetime. So it is not the case that most people with lung cancer, or most never-smokers with lung cancer, would be expected to have an inherited T790M mutation and a strong familial risk of lung cancer. In fact, in the far more common subset of never-smokers who have an activating EGFR mutation on exon 19 or 21 of the EGFR gene, but not a T790M mutation on exon 20 when they're diagnosed, that should essentially rule out that the person with lung cancer has an inherited T790M gene/familial risk of lung cancer.

-Dr. West

Hi Bob,

No, although I certainly understand your concern. This discussion relates only to the inherited T790M EGFR mutation, which although pretty rare greatly increases a person's chances of developing lung cancer. That's distinguished from a lung cancer whose development was driven by an acquired EGFR mutation, which is much more common and is not inherited. That is what our wives had. Acquired EGFR mutations are detected in the cancer cells themselves.

Please know that you remain in our thoughts, with hopes that you are well.

JimC
Forum moderator