EGFR+ Exon21 nvr smoke 54 YO Asian female stage 3 taking Durvalumab?

Portal Forums Cancer Treatments / Symptom Management Immune-based Therapy / Vaccines EGFR+ Exon21 nvr smoke 54 YO Asian female stage 3 taking Durvalumab?

This topic contains 75 replies, has 5 voices, and was last updated by  onthemark 2 days, 5 hours ago.

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June 29, 2018 at 1:57 pm  #1294692    
catdander forum moderator
catdander forum moderator

There were 43 egfr + patients in the study 39 of which were in the durvalumab group. That’s a pretty small number but could suggest one way or other for more followup in that population.

I’m sure Dr. Kelly isn’t the only one with that opinion. But she’s the one writing for asco who I believe are a little more conservative in interpreting data.

I imagine the different interpretations are due to the immaturity of data and the lack of understanding of the drug and even newer treatment.

The thing I find interesting is that it’s believed the checkpoint inhibitors work differently when following chemo/rads.

June 29, 2018 at 1:59 pm  #1294693    

onthemark

Hi Cubety,

EGFR+ patients are more likely to be never smokers than random, so once again you cannot just multiply these probabilities because the events are not independent.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 29, 2018 at 5:10 pm  #1294696    

cubety

catdander and onthemark, an important note that should be mentioned:

I believe in the Pacific study one critique was that the placebo group PFS and OS were lower than what would normally been expected from a representative sample of stage 3A/B non-resectable patients.

So the figure 2 bars potentially somewhat over express benefit in all groups due to this IMO. It may be a reason Dr Kelly gave her opinion in the manner she did (bringing into consideration the low bar set by the placebo group which would mean all groups shifted a little to the left than what would have happened had the placebo group performed more normally). I’ll try to find where I was reading the Pacific study’s placebo group underperformed on PFS and OS. Regardless, the overall results are still a major major advancement for a lot of people. Wait, I think this is it:

https://www.targetedonc.com/case-based-peer-perspectives/lung-cancer/wakelee-locally-advanced-nsclc/stage-3-unresectable-nsclc-the-pacific-trial

Here is the relevant part to my slight concern:

“The progression-free survival for the patients getting the durvalumab was in excess of 16 months. For those getting the placebo, it was less than 6 months. One of the criticisms of the trial was that the placebo group did seem to underperform historical controls. There are a lot of questions around that—some of which are around the high numbers who had weekly carboplatin/paclitaxel without any consolidation. Carboplatin/paclitaxel—we don’t really know the answers.”

Again, thank you for the continuing help as this will be something many people will be pondering with EGFR+ mutations going forward having nonresectable stage 3 disease.

June 29, 2018 at 5:11 pm  #1294697    

cubety

Having a heavy smoker and former smoker representation in the study at 91% might be one reason there was a bit of underperformance in PFS for placebo group but that’s just a guess.

June 29, 2018 at 7:00 pm  #1294698    

cubety

Ah it was Dr Marina C. Garassino,a well known person in the field mentioning not using immunotherapy on never smoker EGFR+ people. Here is the exceprt regarding treating EGFR never smokers:

Could immunotherapy be used for patients with driver mutations?

“This is a very interesting story. If we look to the subgroup analysis of all randomized clinical trials, there is no clear benefit in never-smokers or EGFR-mutated patients. Therefore, it is difficult to say whether it is better to treat these patients with immunotherapy or chemotherapy. We have just a few data coming from the ATLANTIC trial with Imfinzi. In the ATLANTIC trial, patients with EGFR and ALK translocation were selectively treated with Imfinzi at the standard dose every two weeks. In ALK-translocated patients there was no benefit, but in EGFR-mutated patients, who were PD-L1-positive — more than 25 percent — there was a good PFS and a very good OS. I am going to present the results of the expanded access in Italy with Opdivo, where there is some benefit in EGFR-mutated patients.

My personal opinion is that immunotherapy is not the best treatment for these kinds of patients because they have a low mutational burden, but we do not know clearly about the further lines.”

Here is link to article full discussion:

https://www.curetoday.com/articles/expert-discusses-immunotherapys-expanding-role-in-lung-cancer-treatment

I would add that as I recall the EGFR+ responders in Atlantic (group 1 where I think there were 10 EGFR+ responders) mostly were former/current smokers (like 6) and had ultra high PD-L1 expression (I think 8), so again not representative of most never smokers EGFR+ people (smokers tend to have higher PD-L1 expression as I recall).

So Dr Garassino generally expressed not using immunotherapy on never smoker EGFR+ people.

OK back to work, have a good weekend all.

June 30, 2018 at 10:35 am  #1294700    

cubety

Onthemark- sorry I keep wanting to make everything independent with my lack of interpreting data. So with 43 EGFR+, maybe let’s say roughly 25% could be neversmokers EGFR+ (That would be almost 3x the never smoker rate of 9% in whole study participant rates). It seems there may have been maybe roughly 10-11 people under that assumption.

If there were 10 EGFR+ never smoker people, catdander brought up a good point on if any were wild type as they tend to have good response compared to mutant so even one wild could potentially skew EGFR+ response. The high level of smoker population also should skew EGFR+ data favorably vs the never smokers in this study.

When we consider some bias in results potentially on PFS and OS due to the noted underperformance of placebo group (less than 6 months PFS as I recall), it sure seems not difficult to generally assume the EGFR+ mutant neversmokers did not benefit.

Especially knowing both never smokers and EGFR+ people have repeatedly been shown to not respond as well to immunotherapies historically as Dr Garassino noted although this study involves hitting cancer right after chemo/rad.

It is possible (maybe likely) the EGFR+ people in the study’s bar graphs that crossed over to worse than placebo were the never smokers. And with placebo underperformance, those results may have looked better than historical expected ‘normal’.

Thank you for all the input, hopefully we receive some deeper more informed thought from expert opinion looking at things such as the smoker population over representation and the placebo group underperformance.

Also wondering how it relates to a path forward for those that were not in focus in the study- never smoker EGFR+ people, especially knowing the never smoker population unfortunately continues to grow in number and therefore % representation of this disease moving forward.

Durvalumab is a huge step forward for a lot of stage 3 NSCLC people but maybe not all.

June 30, 2018 at 11:04 am  #1294701    
Dr West
Dr West

This is a legitimately controversial question. I would say that a modest majority of experts are of the mindset that the patients with an EGFR mutation were included in the PACIFIC trial, there was a major benefit for the overall trial population, and the subset analysis isn’t compelling enough to say it’s wrong to treat EGFR mutation-positive patients. On the other hand, the minority, which isn’t a tiny minority but probably about 1/3 of thoughtful specialists in lung cancer, who look at the subset analysis that looks like EGFR mutation-positive patients get less or maybe no benefit, and they look at the disappointjng results for immunotherapy in metastatic NSCLC, and then perhaps also factor in the small study from UCLA that I just featured in a video (again, about metastatic disease) and think EGFR mutation-positive patients shouldn’t do durvalumab.

It’s a legitimately controversial question. There is no clear best answer right now. I think it makes sense to discuss the ambiguity with the patient and consider their preferences. None of us should be too dogmatic when there is so little good evidence to inform us. — hence the differences in interpretation of how to fill in the gaps.

Good luck.

-Dr. West

June 30, 2018 at 12:09 pm  #1294702    

cubety

Thank you very much Dr West in clarifying the complicated and split thoughts on decision making for EGFR+ mutation stage 3 nonresectable people when it comes to Durvalumab consolidation therapy.

The Pacific study is certainly an encouraging boost for most nonresectable stage 3 NSCLC people. Hopefully with more time, clarity on the specific subset of EGFR+ (and further for my wife’s specific case never smokers) will be more definitive. Also, hopefully the approach of using consolidation immunotherapy right after concurrent chemo and radiation becomes something that shows more and more promise for future treatment of people with further study.

Looks like we will have a difficult decision to make around mid-late July.

Again, thank you very much Dr West for weighing in (and thank you catdander, onthemark for highlighting and presenting helpful information).

June 30, 2018 at 2:49 pm  #1294703    

onthemark

Thanks Dr. West for clarifying expert opinion.

Cubety, it’s also relevant to consider that your wife might lose eligibility for future clinical trials of immunotherapies (possibly in combinations) if she was already exposed to an immunotherapy like durvalumab. Immunotherapy in EGFR+ patients is still and under-developed area but there is no reason to believe this will continue to be the case in the future.

Plus there are well established treatment lines if she develops evidence of disease after chemoradiation using TKIs like tagrisso. These treatments are only available for EGFR+ patients.

I’ll be happy to write to you privately at inspire about probabilities.

Briefly P(A and B) = P(A)*P(B) if and only if A and B are independent events. Here P is the probability and the symbol * means multiplication.

So event A could be a never smoker with lung cancer and event B could be and EGFR+ person with lung cancer, both drawn from the sample. The probabilities only factor if the events A and B are independent, which they surely are not in most cases and can be proven to be dependent in this particular case.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 30, 2018 at 3:24 pm  #1294704    

onthemark

Cubety,

About the supposedly low PFS in the control arm of the PACIFIC study, this is misleading.

It should be clarified that the PFS of 5.6 months is actually similar to other chemoradiotherapy studies which describe a PFS of 11 months; the PFS was calculated from the time of randomization after completion of chemoradiotherapy in the PACIFIC study rather than upon initiation of chemoradiotherapy (3). The benefit was observed regardless of tumor histology or PD-L1 status. The overall survival (OS) data is not yet mature.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906257/

See:

Immunotherapy after chemoradiotherapy in stage III non-small cell lung cancer: a new standard of care?

The authors go on to write about the PACIFIC trial:

The investigators must be commended for their “all-comers” trial design. The main exclusionary criteria were limited to patients unable to complete conventional chemoradiotherapy, which supports extrapolation of the findings to the general population. As such, it allowed patients to participate with epidermal growth factor receptor (EGFR) mutations and non-smokers, both increasing in frequency in the lung cancer population and known to have lower response rate to immunotherapy (14,15). Of note improvement in PFS was observed in never-smokers, but less so in the EGFR subgroup, raising the possibility that their mechanisms of relative resistance may be different.

From the way this is written, my guess is that the final representation of EGFR, women, never smokers etc. was not by study design but by who was referred to the clinical trial and signed up.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

  • This reply was modified 2 weeks, 5 days ago by  onthemark.
  • This reply was modified 2 weeks, 5 days ago by  onthemark.
  • This reply was modified 2 weeks, 5 days ago by  onthemark.
  • This reply was modified 2 weeks, 5 days ago by  onthemark.
June 30, 2018 at 4:13 pm  #1294707    

cubety

Thank you for your continuing sharing of relevant information specific to my wife and also in many areas more generally to the EGFR+ NSCLC community and how Durvalumab may enter the picture.

It is good to see the extra information on study design, possibly there was a bit of bias in referral given past history of poor performance of EGFR+ mutant type on immunos but guesswork only.

I did find a study showing never smokers had no benefit to Durvalumab but they were treatment naive with only 59 people:

https://www.sciencedirect.com/science/article/pii/S2468294216301265?via%3Dihub

This was the part about never smokers and Durvalumab (again this is small sample size so I am only posting in regards to my wife):

“Most importantly, no clinical response was observed among never-smokers irrespective of PD-L1 expression and histology types, while the ORR in the ever-smokers was 33% for those with high PD-L1 expression and 13% for those with low/negative PD-L1 expression.”

Back to work. Take care. And thank you again… All of this is just my opinion, I don’t wanmt anyone to make any decisions off a message board and am just trying to gather information for our particular case. Well wishes to everyone out there involved in this community.

June 30, 2018 at 6:21 pm  #1294708    

cubety

Interesting reading the different wording of the part you mentioned (non smoker benefit for PFS on durvalumab) with the part I had (never smokers regardless of PD-L1 status or histology having a zero response although that was with a median 8 week treatment on Durvalumab and was retrospective plus not consolidation).

I’m assuming the mention of Pacific trial using the word ‘non smoker’ in your link instead of ‘never smoker’ means they are clinically interchangeable? Not sure but do know never smokers are defined as less than 100 cigarettes in their lifetime (wife has never touched cigarettes and did not grow up in a smoker environment).

On your very interesting highlight of favorable TKI response for EGFR+ mutation and potential future study ineligibility because of previous immuno treatment if we went forward with Durvalumab, I found this from Dr West going back a ways:

“Moreover, it was also known that certain clinical/demographic characteristics, such as being Asian, female, a never-smoker, and having an adenocarcinoma or bronchioloalveolar carcinoma (BAC) tumor histology was associated with a higher probability of a significant response to EGFR TKIs as well . . . ”

http://cancergrace.org/lung/2011/07/23/egfr-mutations-in-adenocarcinoma/

My wife does fit all those categories Dr West brought up and I worry just a bit about what Dr West mentioned in the 2018 Youtube link you provided about small UCLA study that was stopped early when an immuno was being investigated as a first line EGFR+ treatment I think.

I wonder if we do nothing but scans, would a micrometastasis recurrence (likely for her) be of similar origin to her current EGFR+ exon 21 substitution? That would make us a bit more likely to say ‘no’ to durvalumab consolidation. The thought that a likely recurrence could be treatable with a good prognosis of having a TKI treatment on her PFS/OS given history of EGFR+ mutation female Asian never smoker status is a little encouraging.

Take care everyone.

June 30, 2018 at 6:41 pm  #1294709    

onthemark

Hi Cubety

If you look at Table 1 and Figure 2 in the NEJM paper, and look at the columns with the number of patients, you will see that the original authors use non-smokers in figure 2 to be the same patients as never smokers in Table 1. There were 43 patients on durvalumab and 21 patients on placebo. This total of 64 patients is referred to as never smokers in Table 1 and non-smokers in Fig 2.

Although the error bar is large the result seems to exclude statistically the possibility that durvalumab does harm to never smokers as a group. It seems to be a significant benefit looking at Fig 2. In fact the expected result is shifted more to the left than any other subgroup, but again the error bars are large because of the small subgroup size.

The article I quoted was using the naming system according to Fig. 2. I don’t think these terms are generally interchangeable though. That’s why the numbers help out here.

The EGFR+ subgroup also has large error bars but is shifted more to the right and cannot exclude statistically that as a group durvalumab does more harm than good.

Thank you for digging up Dr. West’s quote on the favourability of TKI treatment for your wife’s situation.

I am not a doctor but if I were in your shoes I think about leaning to surveillance, and go to TKI if there were still evidence of disease at scans sufficiently past chemoradiation. This can buy a lot of time. Possibly years. Then I would look at progress on developments referred to at the end of this publicly available article

Navigating the “No Man’s Land” of TKI-Failed EGFR-Mutated Non–Small Cell Lung Cancer (NSCLC): A Review

publicly available at: https://www.sciencedirect.com/science/article/pii/S1476558617304700
[Neoplasia, Volume 20, Issue 1, January 2018, Pages 92-98. open access]

Edited to ad: From what I have read activating mutations do not go away with treatment. Rather, what happens is that new mutations accumulate.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

  • This reply was modified 2 weeks, 5 days ago by  onthemark.
  • This reply was modified 2 weeks, 5 days ago by  onthemark.
  • This reply was modified 2 weeks, 5 days ago by  onthemark.
  • This reply was modified 2 weeks, 5 days ago by  onthemark.
June 30, 2018 at 8:11 pm  #1294712    

cubety

onthemark, luckily we still have weeks to decide. One semi-small worry I would have is if my wife harbors BIM protein deletion. This deletion is rare in Caucasian populations but is close to 15% in Vietnamese population I believe.

Here is a real quick blurb on BIM. I think BIM deletion potentially interferes with TKI’s mechanism to inhibit EGFR mutation cell growth.

http://europepmc.org/articles/PMC4132037

On another note, the Dr West UCLA study video you linked to me mentioned one responder that did quite well on an immunotherapy drug and that it was found out they were wild type. Possibly the Pacific trial had a few wild type and they were the reason for such a large slant to the left in response (I have no idea but have not been able to locate whether any EGFR+ people were wild type in Pacific)?

IF that were the case, it would beg the question in my mind do EGFR wild type people look to have an oversized boost to immunotherapy potentially compared to mutated and maybe even some other NSCLC forms?

Thank you again for your very thorough and thought provoking information!

  • This reply was modified 2 weeks, 5 days ago by  cubety.
  • This reply was modified 2 weeks, 5 days ago by  cubety.
  • This reply was modified 2 weeks, 5 days ago by  cubety.
  • This reply was modified 2 weeks, 5 days ago by  cubety.
June 30, 2018 at 8:22 pm  #1294715    

onthemark

Hi Cubety

“Wild type” just means the person doesn’t have the mutant form. In the case we are discussing it means that all the people who are not EGFR+ are “EGFR wild type”.

Thank you for mentioning BIM. I’ll look into it as it is not something I am familiar with.


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

June 30, 2018 at 9:19 pm  #1294716    

cubety

Thank you for clarity on EGFR wild type, I have a steep learning curve process to go thru :). It does make the far left responders look interesting given the history of EGFR+ mutations and immunotherapy generally.

July 1, 2018 at 8:49 am  #1294720    

onthemark

Hi Cubety,

I also found the same range of percentage of Asian people with BIM deletion polymorphism. But it seems to be an open question whether it affects clinical response to TKIs and overall survival for all populations. See the June 2015 publicly available research paper which looked at a relevant cohort for your wife in Korea:

The BIM Deletion Polymorphism and its Clinical Implication in Patients with EGFR-Mutant Non–Small-Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors

https://www.sciencedirect.com/science/article/pii/S1556086415330410

The majority of patients were younger than 65 years (74%), female (68%), never smokers (76%), and had stage IV NSCLC (67%). There were no associations between the BIM deletion polymorphism and clinicopathological features including gender, age, smoking status, histology, stage, and number of metastasis sites. Patients with and without the BIM deletion polymorphism had similar objective response rates (91 vs. 84%, p = 0.585). Progression-free survival and overall survival did not differ significantly between patients with and without the BIM deletion polymorphism (median progression-free survival 12 vs. 11 months, p = 0.160; median overall survival 31 vs. 30 months, p = 0.452). Multivariate analysis identified significantly predictive markers for clinical outcomes of EGFR TKIs including Eastern Cooperative Oncology Group performance status 0–1, adenocarcinoma histology, recurrent disease, and EGFR mutation type. The results were validated in an independent cohort of 69 NSCLC patients.

Conclusions
It remains to be determined whether the BIM deletion polymorphism provides intrinsic resistance or decreased sensitivity to EGFR TKIs in EGFR-mutant NSCLC patients.

It might be worth having a look at the papers that cite this one and are more recent here:

https://scholar.google.com/scholar?cites=12633231255172724802&as_sdt=2005&sciodt=0,5&hl=en


10/2015 Chest xray found a nodule as part of a physical (no symptoms).
01/2016 Upper left lobe lingula preserving lobectomy stage 2b for 1.9 cm invasive adenocarcinoma with additional 2 mm AIS nodule found in pathology.
03-05/2016 Sixteen weeks of adjuvant cisplatin/vinorelbine.
07/2016 Durvalumab adjuvant clinical trial discontinued after 1st dose knocked out thyroid.
12/2016 Revised to stage 1b (due to VPI) after new guidelines for multifocal lepidic lung cancer.
07/2019 Next scan.

July 1, 2018 at 8:53 am  #1294721    
JimC Forum Moderator
JimC Forum Moderator

Terrific discussion here, to which I’ll just add a couple points.

As far as Dr. West’s older comment about the better response to EGFR TKIs, this goes back to the early days of Iressa and Tarceva therapy, before EGFR mutation testing became widespread. Trials had shown a better response among patients who were non-smokers, asian and/or female. It turns out that is because activating EGFR mutations are more prevalent among those groups of patients. So although Dr. West’s comment is still true, it’s the presence of an activating EGFR mutation that predicts good response to an EGFR TKI. As Dr. Melissa Johnson stated a few years ago:

The IPASS (Iressa Pan-Asian Study) affirmed the hypothesis that Asians never/light smokers with EGFR mutations had better outcomes than when patients with EGFR mutations are treated with chemotherapy.

I’d only add that there were other older studies dating back to 2004 when Tarceva and Iressa were still in clinical development which focused our attention on this group of patients to begin with…two groups in Boston and one group in NYC took the tumor tissue of the patients on the clinical trials testing Tarceva and Iressa who responded best to these drugs, and found that what these patients had in common was a mutation in EGFR. Then, the investigators described the clinical characteristics that collectively described these patients: more likely to be Asian, more likely to be never-smokers, more likely to adenocarcinoma or BAC histology. I guess you might say, that’s where the story really began…http://cancergrace.org/forums/index.php?topic=10629.msg85730#msg85730

As far as the use of the terms “non-smoker” and “never smoker”, it is not helpful to use those terms interchangeably. “Non-smoker” includes those who have quit smoking, and it’s more accurate to consider such patients in terms of their total smoking history.

[continued}


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

July 1, 2018 at 8:57 am  #1294722    
JimC Forum Moderator
JimC Forum Moderator

[continued]

As Dr. West pointed out:

We do know that the lung cancers in never-smokers tend to be more genetically simple than those of long-term smokers, and this makes sense: without the mutagenic (“mutation-inducing”) effect of cigarettes, which tend to lead to cancers caused by a critical mass of multiple genetic insults over time, lung cancer in never-smokers tends to occur more directly by getting a direct hit through a random mutation on a critical signal in cell growth and division, such as EGFR, EML4-ALK, or others yet to be identified. That’s also why the lung cancers in never-smokers in lung cancer may have an “Achilles heel” if you can find and turn off the switch with an EGFR or ALK inhibitor, while our gains against smokers in lung cancer tend to be more “chipping away” than dramatic shrinkage. They have multiple drivers and aren’t amenable to being turned off with a single mechanism. But of course, mutations don’t just pile up at the time you light your 100th cigarette (since “never-smoker” status is defined as having smoked fewer than 100 cigarettes in a lifetime); instead, there are plenty of people who smoked very little a long time ago and just happened to get a lung cancer like that seen in a never-smoker. So there’s likely a spectrum of people with one or a few very important mutations on one end and many, many less significant mutations all added together as the other extreme. So smoking status is more of a continuous variable (can be anywhere in a range, like height) than a discrete variable (like being pregnant or not).

In fact, that’s what the relatively scant evidence shows us. Several years ago, the folks at Memorial Sloan-Kettering Cancer Center (MSKCC) published work from their own more detailed analysis of smoking history, which recorded both “pack-years” (the product of average number of packs per day x number of years smoking) and time since a patient quit, if applicable.

[continued]


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

July 1, 2018 at 9:00 am  #1294723    
JimC Forum Moderator
JimC Forum Moderator

[continued]

Patients were tested for the EGFR mutation, and the investigators found that never-smokers had the highest rate of having an EGFR mutation (51%) (yes, we knew that), but also that ex-smokers had a higher rate of the EGFR mutation than current smokers (19% vs 4%). All of these numbers are higher than seen in some other North American studies, probably because of some self-selection of patients who head out to MSKCC (patients with EGFR mutations are more likely to seek an opinion there). But also quite importantly, patients who quit smoking many years ago had a higher probability of having an EGFR mutation than people who quit smoking just a few years ago…http://cancergrace.org/lung/2009/11/23/smoking-as-a-continuous-variable/

JimC
Forum moderator


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

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