GRACE :: Lung Cancer

Bronchioloalveolar Carcinoma (BAC)

Biomarkers Predicting Clinical Benefits for BAC Patients Receiving Tarceva

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Continuing with the analysis of a publication about tarceva (erlotinib) for patients with advanced BAC that I introduced in the last post, we’ll turn now to the analysis that Dr. Vince Miller and colleagues did on the biomarkers that might predict more or less clinical benefit with an EGFR inhibitor like tarceva (abstract here). The trial looked at three different ways of measuring EGFR:

1) EGFR activating mutations in the gene, which are located in the part of the EGFR molecule where drugs like tarceva and iressa (gefitinib) work, and which have been associated with a high likelihood of response to these agents

2) EGFR “copy number”, which measures overall amplification of the number of copies of the gene in cancer cells, and which at high levels has been shown by some groups to be associated with a higher likelihood of response and prolonged survival than low/normal levels; this was measured here by “chromogenic in situ hybridization, or CISH, similar to the more commonly used test called fluorescence in situ hybridization (FISH)

3) EGFR immunohistochemistry (IHC), which measures the amount of the protein on the surface of the cancer cells, and which has been least clearly associated with better or worse results with EGFR inhibitors, at least the oral tyrosine kinase inhibitors like tarceva and iressa.

In addition, the investigators also looked at K-RAS mutations in the cancer, which have been associated with smoking and rarely seen in never-smokers, and they’ve also been associated with resistance to EGFR inhibitors and likely also many types of chemotherapy. K-RAS mutations appear to be associated with resistance and poor response in general, and some people have suggested that EGFR inhibitors not be tried in patients with K-RAS mutations, because responses have rarely if ever been seen in patients with K-RAS mutation-positive cancers.

Of the 101 patients with advanced BAC and treated with tarceva on the trial, 82 had enough tissue for at least one of these biomarker studies, and 61 had enough tissue collected to perform all four studies. As with several prior studies that have looked at EGFR mutations, the 22% of patients with EGFR activating mutations (higher than expected for a North American population, probably because EGFR mutations are more common in BAC than in lung cancer in general) had a response rate (RR) of 83%, compared with only 7% for patients without EGFR mutations (“wild type”). This highly statistically significant difference was also mirrored by a significantly longer median progression-free survival (PFS) among EGFR mutation-positive patients (13 vs. 2 months), but the difference became attentuated and wasn’t statistically signficant for median overall survival (OS) (23 vs. 17 months). Gene amplification by CISH showed the same pattern, but not as dramatically: those patients with EGFR gene amplification by CISH showed a significantly higher RR (43% vs. 13%) and median PFS (9 vs 2 months), but no significant difference in median OS (25 vs. 16 months). And EGFR IHC really didn’t show any trends at all for any of these efficacy parameters.

Meanwhile, K-RAS mutations showed what they have tended to: a significant difference in RR, with responses never seen in patients with a tumor harboring a K-RAS mutation (0% vs. 32%)), but no significant differences in median PFS (4 vs. 5 months) or median OS (13 vs. 21 months). As you can see from some of the differences in the numbers, however, the small numbers of patients being compared kept some pretty big differences from being what would be considered “statistically significant” (the larger the trial and the number of people available for comparison, the smaller the differences in outcomes need to be in order to be considered overwhelmingly unlikely to be caused by chance alone).

Another interesting way of looking at response is with a “waterfall plot”, in which measured changes in the volume of the cancer with treatment are plotted from largest progression on the left to greatest shrinkage on the right, making what looks like a waterfall. The bars that go downward represent a response (anything from minor to major), and the upward bars are progression:

BAC Biomarker waterfall plot

(Click on image to enlarge)

There are several interesting points here. First, most of the best responses were seen in patients with EGFR mutations, but not all. Second, many of the patients with EGFR mutations also were positive for EGFR by CISH. Third, even though there were no responses among patients with K-RAS mutations, there were patients with these mutations who demonstrated stable disease. Finally, at least half and I would say closer to two thirds of patinets experienced no change or some degree of shrinkage on tarceva, even though the response rate overall was 22%. And we know that survival can be improved in populations with stable disease.

Another interesting issue, though it isn’t addressed here, is that we’ve seen that survival is best for patients with EGFR mutations, apparently no matter what treatment they get. So though we would think that a drug like tarceva or iressa would be the critical driver for improved survival in patients with tumors that have EGFR mutations, they actually seem to just do better overall, so it may be a marker of a generally more responsive and/or slower-growing cancer. The opposite is seen with tumors that have a K-RAS mutation (and we have almost never found a tumor with both an EGFR mutation and a K-RAS mutation): they are not only resistant to EGFR inhibitors, but they also appear to be resistant to conventional chemo as well and just appear to do worse overall.

Although I think the biomarker story is interesting, I would argue that the results here show that you don’t need to have an EGFR mutation to respond, that survival is not significantly better for EGFR mutation patients or any other biomarker, and that patients with tumors that show K-RAS mutations may not respond but may show stable disease on tarceva. Taken together, I think the biomarker story is interesting but wouldn’t really guide my clinical decisions at this point. I wouldn’t only offer tarceva to patients with an EGFR mutation or gene amplification, and I wouldn’t necessarily exclude a patient with a K-RAS mutation from getting tarceva either.

As always, I welcome your thoughts and questions.


Surgery for BAC: Special Considerations

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While there is a lot of variability in the clinical behavior of bronchioloalveolar carcinoma (BAC), there are some commonly observed findings that are now leading lung cancer experts to consider it as a distinct clinical entity worthy of special consideration for management. Among the important areas for potentially special clinical management is in surgical management of early stage disease. As noted in the last post, the most well differentiated BAC lesions have a very low likelihood of demonstrating nodal spread and have a remarkably high survival at 5 years, approaching 100%. However, they can be multifocal through the lungs and are sometimes managed by multiple surgical resections over many years. With that potential to have small, slow-growing lesions emerge over many years and even over decades, but with a very finite amount of lung tissue to work with, BAC lesions have been a leading consideration for smaller, sublobar resections as an alternative to a full lobectomy (see summary of options in post here) that has generally been the default cancer surgery for lung cancer.

Several of the leading thoracic surgeons in the world, particularly those with an interest in BAC and smaller surgeries, converged in NYC in November of 2004 as part of the first “consensus conference” on BAC (I participated on a committee that focused on systemic (whole body)therapy for advanced BAC) to discuss the state of the art and most relevant management questions, from which they produced a report (abstract here). Largely from a collection of Japanese retrospective studies of early stage BAC, a clear picture has emerged. First, lesions that appear on CT as hazy ground-glass opacities (GGOs) appear to represent noninvasive BAC, while the solid component on CT scans is highly likely to represent invasive adenocarcinoma. Second, smaller lesions (2 cm and smaller) that are predominantly GGO on CT, BAC under the microscope have a remarkably good survival and an exceptionally low likelihood of node involvement.

On the basis of this work, a couple of trials are now being conducted to ask whether small lung cancers can be treated as well with sublobar resections as a full lobectomy. One of these is being conducted in Japan, looking specifically at adenocarcinomas less than 2 cm. A US-based trial, CALGB 140503, is now active and randomizing 1300 patients with peripheral lung cancers up to 2.0 cm to receive either a lobectomy or sublobal resection. The CALGB trial is being conducted with the participation of the other cancer cooperative groups throughout the US, meaning that we’ll be asking this question for a few years to come. In the meantime, lobectomy remains the standard approach for resectable lung cancer, but if there are a subset of people who may be the best candidates for smaller surgeries, who may have cancers least likely to need extensive resection and perhaps most likely to benefit from the sparing of lung tissue that would be valuable to continue to have later, especially if additional lesions need surgery in the future, as may well occur with BAC.


Noguchi Classification of Bronchioloalveolar Carcinoma (BAC)

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I had previously written about a spectrum from pure bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma in one of my first posts here, but the real credit for this concept goes back to Dr. Masayuki Noguchi from the National Cancer Center Hospital in Tokyo, Japan, who characterized a classification system for peripheral lung adenocarcinomas back in 1995 (abstract here). This paper led to the “Noguchi” system of grading the more typical adenocarcinomas from A to D, with some important implications. While other proposed classification systems have been developed, and none is uniformly accepted and used, the Noguchi classification system comes up more than others in describing the continuum I alluded to previously that progresses from pure BAC to invasive adenocarcinoma.

Obviously, this was a Japanese study, which has important implications, because the Japanese world of lung cancer i(LC) s different from that in the US or Europe. In Europe, LC is still very disproportionately male, related to tobacco, and about 50% squamous cancers, while Japan is the other extreme, with some studies showing a closer balance of women and men, 30-50% of patients as never-smokers, and remarkably few cases of squamous cancer, with LC being comprised of generally adenocarcinoma and its well-differentiated subset. A North American population generally shows results between these two extremes.

The Noguchi study involved a detailed analysis of 236 patients with peripheral adenocarcinoma lung tumors (near the outer edges of the lung), all 2 cm or less in diameter. The specifics of the grading system and the definitions of the classes are complex and worth knowing only if you’re a pathologist carefully reviewing tissue and describing lung tumors. The important the highlights are that groups A to D are far more common than rare adenocarcinoma subtypes known as tubular and papillary adenocarcinoma, and also that there is a gradation from A to D of most differentiated to least differentiated. Men comprise the vast majority of group D, while the sexes are much more evenly split in the groups that are well differentiated and would be considered BAC or a variant. The likelihood of finding nodal involvement was also related to the Noguchi group; no patients in groups A or B had any lymph node spread of their cancer, compared with 28% in group C and 48% in group D. In addition, pleural involvement and vascular invasion were significantly more common in groups C & D than in groups A & B. Growth and cell division were also factors, with the rate of cell division far higher for the less differentiated cancers. The number of mitoses (my-TOW-sees), or cells in the process of dividing on a detailed look at the slide, was more than 5 per “high-powered field” in only 6% of groups A & B, compared with 26% for group C, and 53% for group D. But the most important factor, correlating with the rates of cancer cell division, was survival, which was 100% after 5 years for groups A & B, but lower as you move stepwise from type C to type D:

Noguchi OS curves

(Click on image to enlarge)

This type of trend has also been seen outside of just BAC and adenocarcinoma; I’ve written that tumor grade is well correlated with survival (see prior post), and specifically that people with well-differentiated LC do better overall than those people with poorly differentiated tumors.

One other important point is that this study demonstrated that patients with small, peripheral, and very well differentiated lung adenocarcinomas had a survival of 100%, while none demonstrated evidence of nodal spread. This raised the question of whether it’s necessary to do as extensive a surgery in the setting of a well-differentiated lung adenocarcinoma as you would routinely do for other cancers. If the prognosis is outstanding, perhaps we can do smaller surgeries and still achieve such excellent results. I’ll cover the question of optimal surgery for small and well-differentiated lung adenoarcinomas later. This raises the unusual but welcome question in the field of LC, “what is the least we can do to still nearly assure ourselves of excellent results?” Could less be more?


Beyond Stage & Tumor Size: More Pathology Variables Associated with Risk of Recurrence after Surgery

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The decision about pursuing post-operative treatment is often difficult and requires carefully weighing the risks of treatment with potentially challenging and even dangerous chemotherapy against the potential to eradicate micrometastases and actually lead some people to be cured who otherwise wouldn’t be. It’s important to remember that some people are already cured, while others won’t be cured even with treatment. We’re pursuing treatment for the 5-15% higher survival rate at 5 years from adding chemo, presumably representing the proportion of people who have micrometastatic cancer cells that are apparently eradicated by getting 3-4 cycles of platinum-based chemotherapy:

Scagliotti adjuvant chemo explanation

(Click image to enlarge)

The general guidelines we use to assess risk for recurrence include stage of the cancer as the primary focus. I also described the relevance of tumor size as an important factor to stratify risk of recurrence in my recent post on that topic. But there are other potentially relevant factors for people who have cancers that are “on the bubble” about whether they have enough risk to justify the side effects and some real risks of post-operative chemotherapy. Continue reading


The Variability of Bronchioloalveolar Carcinoma (BAC): Non-Mucinous and Mucinous BAC

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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:

Mucinous vs. nonmucinous BAC histology (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:

Mucinous BAC on CT scan Nonmucinous BAC on CT Scan Continue reading


Limited Resections for Very Small NSCLC Tumors and BAC

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While lobectomy or pneumonectomy may be the surgical treatment of choice for most NSCLC tumors in younger, fit patients, a limited resection may be an ideal choice in certain settings. In my previous post I discussed the data supporting a limited resection in older patients, who are likely to have competing health risks that may make it less critical to pursue the most aggressive surgical strategy. Another situation in which a sub-lobar resection may be particularly appealing is when the tumor is quite small and/or has characteristics suggestive of an indolent natural history. In such cases, a lobectomy may be more surgery than is required. There are trials now asking the question of whether patients with the most favorable features based on size or histology (microscopic characteristics) may do as well or better with limited resections than the standard lobectomy or pneumonectomy. Continue reading


The Risk of Overtreating Indolent Bronchioloalveolar Carcinoma

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Bronchioloalveolar carcinoma, or BAC, is a subtype of lung adenocarcinoma that has a tendency to progress more slowly, stage for stage, than other types of lung cancer. There are many patients who experience symptomatic and significant progression over months, and rarely patients have a very aggressive and fulminant form of the disease. However, many patients with BAC experience slow growth that raises the risk of potentially overtreating it, with the possibility of detrimental effects from that.

As someone with a particular interest and expertise in BAC, I see the situation with BAC as being similar to the issues we face with prostate cancer. Once a blood test for detecting prostate cancer emerged (prostatic serum antigen, or PSA), it became possible to identify 200,000 men in the US per year who had prostate cancer. The problem is while a huge proportion of men will develop prostate cancer as they get older, many will have an indolent cancer that will not really threaten their survival, and for which treatment with surgery or radiation can have significant long-term side effects. A low grade prostate cancer is well known for being a cancer men can “die with, but not of”. In other words, men can have a prostate cancer that would never directly threaten them, and they can go on to a ripe old age before succumbing to heart disease or another non-cancerous condition. Continue reading


EGFR Tyrosine Kinase Inhibitors in Advanced BAC

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As we established several years ago that it is indeed possible to do clinical trials with more than 50 or even 100 patients with advanced BAC, we were also seeing that those first forays into advanced BAC with standard chemotherapy were somewhat disappoingting (described further in another post). Fortunately, as it became clearer that we needed other options for advanced BAC, we started to see the first cases of patients with BAC who received Iressa on clinical trials who would sometimes have rapid and profound responses to this drug (below showing a difference after just 5 days):

BAC pre and post iressa

The lung cancer physicians at Memorial Sloan Kettering Cancer Center (MSKCC) reviewed the results from 139 patients who received the EGFR tyrosine kinase inhibitor (TKI) Iressa (gefitinib) as a single agent over a 5 year period and found that a diagnosis of BAC was among the strongest predictors for having a response to Iressa (abstract here).
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Chemotherapy in Advanced Bronchioloalveolar Carcinoma (BAC)

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Up until very recently, conclusions about the usefulness of chemotherapy among patients with advanced, diffuse BAC had generally been based on retrospective experiences with chemotherapy at a single center with a very limited number of patients. From such limited subsets, it is difficult to tell whether BAC is less responsive to standard chemotherapy than other forms of NSCLC, as is widely perceived, or if chemo is similarly helpful for BAC as for NSCLC in general. Some of these studies suggest a similar response rate in BAC compared to other types of NSCLC, while others suggest that patients with BAC are less likely to respond. Making conclusions has also been a problem because of the difficulty in measuring response of BAC lesions, which are often poorly circumscribed on CT scans that are generally used for response assessment. Continue reading


Defining Bronchioloalveolar Carcinoma (BAC): One End of a Spectrum

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The clinical syndrome of BAC is characterized by spread primarily through the lungs, a higher proportion of never-smokers or light former smokers, a greater proportion of women, and often progresses more slowly than most other lung cancers. This clinical and radiographic (scans) scenario isn’t necessarily seen only with “pure BAC” under the microscrope from a biopsy, but rather can be a spectrum from pure BAC to part non-invasive BAC pattern and part invasive adenocarcinoma, and on the other end of the continuum is invasive adenocarcinoma, as shown in the illustration of how these appear under a microscope.

Pure BAC Adenocarcinoma w/BAC Features Invasive Adenocarcinoma
Pure BAC Adeno w/BAC Features Invasive Adeno

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