Lung Cancer / Mesothelioma
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Loading ...One of the themes that we’ve covered in some of the posts introducing the clinical entity of BAC is the variability in its natural history. In fact, much of what we’ve been learning about BAC has been in the last several years, and we’re still learning more about it all the time. One of the things we’ve struggled with is the range of outcomes, that some patients can experience rapid deterioration and no response at all to EGFR inhibitors, while other patients can have a remarkably slow progression, and they sometimes will have an astounding regression of disease from EGFR inhibitors. It sometimes seems as if there are at least a couple of diseases being labelled as BAC. In fact, that’s the case, and it’s been part of the confusion in why some people don’t fit a simplified view of what is supposed to happen in BAC. So let’s talk about mucinous and non-mucinous BAC.
Non-mucinous BAC is the largest group, accounting for about 40-60% of the patients, while perhaps 30-40% have mucinous BAC, and about 10-15% fall in between and are classified as mixed or indeterminate. In truth, this is pretty high-level classification that is not always (or even often) mentioned in pathology reports of BAC, and I would consider it relatively unreliable if read from a small amount of tissue and/or read by a pathologist without much expertise in lung cancer. In truth, even expert pathologists differ in how they interpret BAC diagnoses. Here’s a slide of BAC and adeno subtypes under the microscope:
(click to enlarge)
Mucinous BAC is the subtype that is associated with a cough productive of thick sputum, and it tends to appear more localized and pneumonia-like on CT scans than non-mucinous BAC, which appears most commonly as a buckshot appearance of lots of tiny, diffuse nodules:
There is a pattern, sometimes considered a separate stage, of BAC that is called the pneumonic form, and this is characterized by one lobe being filled throughout with BAC (abstract here). This is a mucinous subtype, and it has been identified as being a particularly challenging form of BAC. Because it is confined to a single lobe, surgery is sometimes performed, either because that is the only area involved with disease or because the cough is so bad that patients want surgery in order to feel better by removing the affected area of lung. Unforutnately, this pneumonic form typically recurs within just a few months, and our therapies for it like EGFR inhibitors and chemo have been disappointing.
There are some patterns emerging that appear to have relevance to how we treat BAC. EGFR mutations are seen almost exclusively in patients with the non-mucinous form, in which they appear in approximately 20-25% of cases (abstracts here, here, and here). The numbers are higher when testing for gene amplification for EGFR as determined by fluorescence in situ hybridization (FISH), in which 44% of non-mucinous BAC tumors were EGFR FISH-positive, vs. just 4% for mucinous BAC (abstract here). In contrast, K-ras mutations are seen more frequently in resected mucinous compared with non-mucinous BAC (abstract here), and I’ve described previously how the evidence is converging that the tumors with K-ras mutations are highly unlikely to respond to EGFR inhibitors.
In fact, the results with EGFR inhibitors are consistent with what these studies would predict. The response rates of patients with Iressa for advanced BAC (abstract here) actually showed a response rate of 30% and another 40% with stable disease among patients with non-mucinous BAC, vs. no patients with mucinous BAC showing either a response or stable disease, and actually all showing progression as their best response on Iressa (only a subset of patients on the trial had enough tissue for this assessment, so the numbers are small). Another trial using Iressa for BAC also found a higher progression-free survival, disease control at 3 months, and response rate among the patients who had non-mucinous compared with mucinous BAC (abstract here).
On the other hand, in the very limited information we have about chemo for BAC, 19% (3/16) of the patients with mucinous BAC responded to taxol (given over 4 straight days as a slow IV infusion, which has fallen out of favor), compared with no (0/13) patients with non-mucinous BAC (abstract here). There isn’t a lot of information here, but it does suggest that patients with mucinous BAC may be better served by pursuing conventional chemo rather than immediate EGFR inhibitor therapy, which is commonly recommended as first-line treatment now for advanced BAC.
In fact, the ex-smoking woman with the CT images used above to illustrate mucinous BAC came to see me a few months ago, with a very rapid progression over the preceding few weeks to months, in terms of shortness of breath and weight loss. She was declining so quickly we felt a great need to start treatment on her, which was complicated by the fact that she was quite weak and debilitated. I started her on tarceva, because it is now becoming an attractive early standard for BAC, and also because I suspected I’d be able to tell very quickly whether she was responding or not. Also, because the responses to tarceva can be so dramatic and long-lasting, I didn’t want to have her miss the chance to be a major beneficiary of it. However, she didn’t respond, and she continued in that tailspin, as I thought she might, given that this was mucinous and that she had a significant smoking history. Within a very short time I stopped her tarceva (far shorter than I would usually do, but she wouldn’t survive the usual two month test), and I started her on carbo/taxol/avastin. While it hasn’t been miraculous in terms of response, she definitely came out of her tailspin, gaining weight and now off of oxygen. At this point, I’m not sure if it’s the chemo, the avastin, or the combination, but I’m encouraged to have seen a patient turn around from a startling decline with something other than tarceva. It suggests to me that, along with the small amount of evidence we have from the taxol trial noted above, mucinous BAC may be better served by a chemo-based approach, and perhaps the avastin is a significant help.
The Southwest Oncology Group is just now starting a trial that I’m leading, known as SWOG 0635, that will enroll patients with BAC (mucinous or non-mucinous, also including adenocarcinoma with BAC features) to receive the combination of tarceva and avastin, which we expect will be first-line therapy for most patients. We’ll be looking very closely at differences based on histology. Perhaps the avastin provides a key benefit for patients with mucinous BAC that will lead to better results for this combination than tarceva alone. Perhaps the avastin/tarceva combination will lead to even better results with tarceva for the population with non-mucinous BAC, who already seemed to benefit considerably as a group from EGFR inhibitors alone (as avastin improved outcomes vs. chemo alone for advanced NSCLC in general). For now, we don’t know, but we’re learning more, and much of that is from looking more carefully at what we’ve done and trying to discern patterns that can be lost by pooling the results. It really does look like BAC encompasses more than one disease.
Posted in: Bronchioloalveolar Carcinoma (BAC), Bronchioloalveolar Carcinoma (BAC), Chemotherapy, Core Concepts, EGFR mutations and other molecular markers, Epidermal growth factor receptor (EGFR)-based therapies, First-line treatment, Lung Cancer, Non-Small Cell Lung Cancer (NSCLC), Pathology/Lung Cancer Subtypes, Second-line treatment, Special Populations in Lung Cancer, Stage IV/Advanced/Metastatic NSCLC, Targeted therapies, Third-line therapy and beyond, Treatment
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Hello Dr. West,
Thank you for this fascinating post and for the forum as a whole.
To start, I have a question about the ease (or difficulty) doctors have in distinguishing between adenocarcinoma with BAC features, non-mucinous BAC and mucinous BAC. For the latter two, are we only looking for productive coughs, or can we see a difference in the cells as well?
My father has a dx of adenocarcinoma with BAC features, but should we get a second opinion on the dx as well as the on the treatment? There seemed to be some confusion in the hospital (and a complete lack of sublety) about what form of these NSCLC’s my father has. Obviously, this will affect treatment choices, but I’m not sure that the general hospital where my father started gets is prepared for these sorts of nuances. The oncologist he was referred to did not get the pathology slides in addition to his scans and xrays, so I’m a bit worried that they took the dx for granted…and, if it is a false assumption, I’d like to root it out now.
My father had a non-productive cough for months that he attributed to “smoker’s cough,” and I tend to believe that he had cancer well before the official dx…and that just because a non-productive cough turned into a productive cough, we cannot conclude that the cancer type changed.
Hope this makes sense. Apologies if I am not clear…very new to all of this and just wanted to kick off the discussion and go from there.
Best,
Yirol
yirol
P.s. When I try to enlarge the CTscans (?) on the right, I only get a summary page again with no enlarged images. Can you help? Thanks!
yirol
Also, in re-reading my post, I’m not sure I’ve been clear, so let me try again with a very banal sentence or two:
I believe my father has had cancer for years prior to the official diagnosis. I can remember him coughing disturbingly for years. It was always a dry, non-productive cough (and, sadly, we did not rally to force him to the doctor because he hated even our pleas that he stop smoking). About 3-4 weeks prior to an official dx, however, the non-productive cough changed to a productive cough that anti-biotics did not clear up. Of course this doesn’t mean that a pathology of non-mucinous BAC turned into a pathology of mucinous BAC just because the symptoms changed, right? And the change/progression of the symptoms does not necessarily prove a finding of adenocarcinoma with BAC features, right? What info are we to rely on for an adequate and sufficient dx? Besides the CTscans you show above, can you possibly post cell pathology for each of these NSCLC’s (Adeno w/ BAC feat., non-mucinous BAC, mucinous BAC). I’m finding this very confusing. Also, is it typical to have a delay in dx because these NSCLC’s resemble pneumonia and T.B.? We went on those goose chases twice (very frustrating!).
Okay…more than a sentence or two. Thanks for your time and patience.
Yirol
yirol
Yirol,
Thanks for pointing out the picture problem. There was some server glitch where a few of the pictures from posts got switched around. I’ve never seen that before, and I hope it doesn’t happen again. If it does, I’ll whine about it and we’ll figure out what the problem is. The pictures should all enlarge now and are all correct at this time, from what I can tell. I added a slide with images of mucinous and non-mucinous BAC under the microscope.
I will emphasize that diagnosing the exact BAC diagnosis is VERY challenging, even among expert pathologists, and unquestionably among non-experts. I must confess that after working with many BAC patients for several years, I’m going as much by the patterns, clinical and radiographic (CT images), as I am by a precise appearance under a microscope. However, I don’t think there’s a transition from non-mucinous to mucinous — they’re just different diseases. So if your dad had increasing symptoms over time, I would speculate that it’s because of the increasing amount of lung involved with his cancer. And while it’s hard to know the time line without seeing more evolution over time, I would consider it quite possible and perhaps likely that many BACs have been ongoing for months to years before diagnosis. However, if they’re going on that long:
1) it suggests an indolent natural history, because it allowed a person to remain minimally symptomatic and very slowly progressing clinically for all that time, and
2) it’s also quite commonly a multifocal (in more than one place) disease all along, so it’s not necessarily the case at all that finding it earlier would provide more treatment options.
In fact, being able to see how a cancer has changed or not over time is very helpful for me in trying to determine the pace of disease and allows me to recommend treatment options better.
It can also be hard to determine whether someone has “pure BAC” or that spectrum of some invasion and some pure BAC. However, if there’s spread outside of the chest, such as involving bone or liver or somewhere else that isn’t lung, then this means that the cancer must have invasive capability to spread, so it shouldn’t be pure BAC but must have at least some invasive adenocarcinoma component. Practically speaking, though, we see that some people with adeno/BAC mix respond very well to EGFR inhibitors, so we’re generally including patients with either pure BAC or an adeno/BAC mix to go on trials designed for patients with BAC.
Please just let me know if I missed other questions.
-Dr. West
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