Relapse HISTORY for her2+S

[karenann]

Susan,

Was your onc talking about being node negative and not needing Herceptin? I have never heard that Herceptin has no value for er/pr+ bc.

I have the same pathology as you, 1.3cm tumor, er/pr+, grade 3, node negative and Her2+++. I did dose dense AC & T and just completed my year of Herceptin.

I would have changed oncs to get Herceptin.

Just my two cents.

Hugs,

Karen

[AlaskaAngel]

SusanV, Karenann, and Bev,

I realized when reading your posts that we all tend to think primarily in terms of our own situation, not realizing that when we give short answers they are easily confusing, and I'm probably guilty here of that.

In my situation, what my onc was specifically referring to I think was to my question as someone who already finished original chemotherapy that didn't include a taxane, and was asking if I could now have both a taxane and Herceptin (for treatment more than 2 years out from original treatment). He said off the cuff that the taxane mostly really only helped those who were HR-.

Bev and Karenann, I think you were assuming from SusanV's post that she was saying Herceptin wouldn't be helpful to her--but I think she (like me in my earlier post) was not talking about not having Herceptin, but rather talking about whether adding Taxol was helpful, and her onc then told her the same thing mine told me--that adding a taxane works best for those who are HR-.

I hope no one minds if I start a new thread for this. It is getting hard to follow this one because it is so long.

AlaskaAngel

[RobinP]

Excerpts from the Professionals: (from http://www.breastcancerupdate.com/bcu2006/2/default.htm)


DR PRITCHARD: The most interesting piece of data I saw was a curve showing that disease in untreated patients with ER-negative disease recurs quickly in the first few years, but then their curves level out much more than patients with ER-positive disease. On the other hand, untreated patients with ER-positive disease do much better in the first five years, and they’re still ahead in the next five years. However, at approximately 10 years, the disease-free survival curves for ER-positive and ER-negative disease cross over each other, and at 15 years, the survival curves are crossing.

DR LOVE: So the untreated patients with ER-positive disease have a higher delayed relapse rate than those with ER-negative disease?

DR PRITCHARD: Yes. It’s slower and steadier, but they keep recurring. It makes sense that we’re now seeing that treatment after five years can be very helpful, because these patients have an ongoing risk. We haven’t all appreciated this very well until the last few years. I believe that the Saphner paper showed this ongoing risk, and the Oxford Overview data have shown this before as well (Saphner 1996).

We all think of ER-positive disease as having a better natural history, but the fact is that by 10 years, more of the patients with ER-positive disease have recurred than the ER-negative group, both untreated. It’s shocking because we thought we could treat these patients with tamoxifen and after that they would do well and we would not have to worry about them, but they continue on having recurrences.

So I think adding additional treatment with an aromatase inhibitor or certainly evaluating these patients in clinical trials is important.


And more interesting comments on TX. for small tumors; excerpts from the Professionals:

DR LOVE: How do you manage a HER2-positive tumor smaller than one centimeter in the adjuvant setting? DR BURSTEIN: The honest answer is that we don’t know whether these women need trastuzumab. We do need to be respectful of the fact that these women have a better prognosis because their tumors are so small. Certainly for women whose tumors are ER-positive and less than one centimeter, I’ve not offered trastuzumab.

For patients with ER-negative disease, I suppose one could consider trastuzumab, though the quantifiable gains from adding this agent are not known. It would be interesting to conduct a study evaluating trastuzumab with or without chemotherapy in patients with very small tumors. Maybe we can begin to eliminate chemotherapy for the lower-risk patient population if we can alter the natural history of their disease.
__________________
Robin

[AlaskaAngel]

Thank you, RobinP (and Hope for her post as well). I have an appointment coming up soon with an onc who specializes in bc, and I'm glad if my confusion about all of this has opened this discussion for a number of us.

At the same time, it is interesting, ironic, and frustrating to find out that essentially my original question about the combination of Herceptin and a taxane in 2005 at the time of the ASCO presentation (for those who have never had a taxane) was not only common sense but a whole lot more on target than the professional vacuum about it.

AlaskaAngel

[MJo]

I had a tumor of 1/2 centimeter..very tiny...with neg. lymph nodes. Her2++
I took the Oncotype DX test. My score was 32, which is the beginning of the high risk fo recurrence (in 10 years) group. I know Jean's tumor was even smaller than mine, and her Oncotype score was higher. I didn't want chemo, but I felt I needed to take it.

[RobinP]

Good luck AA. I hope I didn't open a can of bad beans for you with this thread about relapse. In general I think that most people's odd of getting bc relapse five years out is more on the downside as evidenced by the various relapse curves that I posted. At the same time, I do think also that the long term relapse rate for her2+ that er/pr+ is very obscure, at this point, which makes it difficult to EXACTLY determine any delayed course of treatment for this group.Note there is not a defined course of delayed treatment for the hormonal negative group, her2+++ group either who never got Herceptin initially. I know, it really sucks, being in this boat.Maybe it's just best to ignore these relapse rates in certain circumstances. I don't know???

Perhaps the relapse data I posted is most useful to those newly diagnosed who are making adjuvant treatment choices now. Often physicians just don't offer this kind of information though, and make all the treatment choices for the patient. However, I think it is important for one to know their risks of relapse straight up so that they can do ALL the appropriate treatments that they feel necessary.

[gin-tx]

Dear Robin,

I think your findings are very interesting and I intend to print it and show to my onc when I go next time. This is my second episode of BC, first was 10 yrs ago, lumpectamy followed by 36 radiation treatments. Now I have developed a problem with other breast, had biopsy in April, surgeon thought everything looked good but it came back malignant. He did sentinel node procedure, wider margins and first lymph node removed was malignant, only one in fact. It was Her2. This followed by a bone scan that revealed something unknown, then MRI that determined I had tumor on spine changing my status to Metastatic Grade IV. Had to address spine problem first, had 18 radiation treatments. Now am doing Herceptin w/Aridia, so far so good, have had 5 treatments. The docs are talking more radiation to breast that has been untreated, I told him I don't think I can handle it. See what mammogram and CT shows next month.

Thank you for your wonderful information. Keep in touch and let me know how you are doing.

ginkott1@aol.com

[karenann]

Robin,

In the article you posted above, it keeps making reference to, untreated er/pr+ and er/pr- patients. Does that mean that these people were not treated with any chemo or herceptin?

Thank you,

Karen

[Hopeful]

karenann,

The article RobinP posted about is from the results of the 2005 Early Breast Cancer Trialists Collaborative Group. Here is a link to the page on their website where you can access the full report: http://www.ctsu.ox.ac.uk/~ebctcg/. You want to go under "Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials" and click on the link for the pdf file "final typescript of the paper with tables and figures."

The information about "untreated patients" means patients who had surgery with or without radiation but neither tamoxifen nor chemotherapy. (The studies do not include any patients treated with herceptin, taxanes or aromatase inhibitors - they were begun so long ago the modern drugs were not in use.) The studies were begun in the early 1980's (I can't imagine a study today where there would be no adjuvant treatment) and the populations have had a chance to mature for 20 years, giving probably the best picture we have now for the natural history of early stage bc. The information shows that hormone negative patients recur largely in the first five years, then their risk begins tapering off. Hormone positive patients have fewer recurrences in the first five years, but the chances of recurrence continues at a steady level out to 10 years and beyond. At the ten year mark and beyond, the risk of recurrence for hormone negative patients is actually less than that for hormone positive patients in an untreated population.

Hopeful

[karenann]

Dear Hopeful (I like your name),

Thank you very much for the information.

My aunt was stage 1, er/pr-, her2-. The only treatment she did was radiation and four year after her original dx, her cancer came back with a vengeance... that's why I threw the kitchen sink at mine, eventhough it was stage 1.

I am hopeful, too.

Hugs,
Karen

[Lani]

16q stands for part of chromosome 16 which contains genes important in survival of breast cancer

Her2ER- tumors are usually in the ERBB2 subtype
her2 ER+ tumors are usually in the luminal B subtype

Figure 5. Expression in 16q across the Sørlie et al., tumor subtypes indicates that the subtypes should be grouped into a high and a low expression group. The difference in average median-normalized expression in 16q was tested between all possible combinations (n = 10) of subtypes. To the left, thin lines indicate a significant difference in means between subtypes, thick lines indicate that there is no significant difference. The corresponding P values are listed to the right.

Table 1. Statistics by Tumor Subtype for 359 Classified Tumors
Basal ERBB2 Luminal A Luminal B Normal-like
N 57 40 118 53 91
ER-positive (%) 2 44 70 97 87 92
PgR-positive (%) 2 53 70 93 77 92
Grade 1 (%) 2 P < 0.001a 4 5 34 6 43
Grade 2 (%)a 22 38 55 38 52
Grade 3 (%)a 75 56 11 56 5
5 years RFS (%) 2 P < 0.001b 68 48 84 57 80
Mean expression in 16q (95% CI)c 0.207 0.209 0.024 0.199 0.023
ANOVAP < 0.001 (0.158-0.257) (0.157-0.261) (-0.011-0.059) (0.144-0.254) (-0.001-0.047)
Statistical tests and associated P-values are listed below the row names, in the case of Elston grade the Pearson 2 test (under Grade 1) refers to a test of all grades versus subtypes.
a Elston-Ellis grade.
b 5 years or more of recurrence-free survival
c For each patient, the average median-normalized expression (log2) for all genes in 16q was calculated. Mean with 95% confidence interval for subtypes, as indicated by column headers.
DISCUSSION

We have investigated the relationship between chromosomal positions and gene expression in breast cancer patients, specifically in relation to survival and the expression-based tumor classification described by Sørlie et al. ([2001], [2003]). Our major finding is a remarkable negative association between gene expression in 16q and survival. The Bonferroni corrected P values for overrepresentation of 16q in the 200 and 500 gene lists were both <2.2 × 10-16. This striking feature of the gene expression in 16q seems local in the sense that a majority of genes in 16q have a tendency for inverse association with survival, as is obvious when studying Figure 2, where the distribution of t-scores for 16q seems shifted to the left. A wider and possibly bimodal distribution for 16q suggests that there is a sub-distribution of genes (to the right) for which the negative association with survival is less pronounced. This sub-distribution, however, seems shifted to the left also; the rightmost part of the curve for 16q indicates lower density at given t-scores than what is indicated for average chromosomal arms. This was also found to be true when the height of the 16q curve was increased to compensate for the lower height of the right sub-distribution (not shown). The division of genes into groups corresponding to chromosomal arms is, at least to some extent, artificial; chromosomal aberrations cannot be expected to honor these boundaries. The overrepresentation approach could however be applied to the same gene lists to test for disproportionate contributions from chromosomal arms and bands, and check for consistency. Interestingly, for the negative association between 16q and survival, the result was quite consistent; 16q22, 16q24, 16q12, and 16q23-24 were deemed significant in the 200 and 500 gene lists. Only one chromosomal band, not located on 16q (20q11) had a significant P value for negative association with survival. There was less consistency in the gene lists positively associated with survival, e.g., the chromosomal bands 8p22-p21 were significantly overrepresented in the 200 and 500 gene lists, but the chromosomal arm 8p was not. A possible explanation for this could be that 16q loss often extends to the entire chromosomal arm, whereas 8p is often subjected to loss and gain/amplification with a breakpoint region in the center of the arm.

To investigate the relationship between gene expression in 16q and other tumor characteristics, we have used an expression estimate for the entire arm. It is reasonable to ask whether this estimate can be informative; are genes on this arm sufficiently co-expressed to make this summary valid? A heat map of the genes on this arm does give that impression (Supplementary Fig. 1; Supplementary material for this article can be found at http://www.interscience.wiley.com.la...-2257/suppmat). The tendency for genes to co-vary in the chromosomal arm is indicated by the SD of the estimate across patients. The SDs for all chromosomal arms (as a function of size) are plotted in Supplementary Figure 2 (Supplementary material for this article can be found at http://www.interscience.wiley.com.la...-2257/suppmat). To assess the probability of the SD given a null-hypothesis of no tendency for coexpression, genes were randomly and repeatedly assigned to chromosomal arms, and SDs were calculated. Supplementary Table 4 (Supplementary material for this article can be found at http://www.interscience.wiley.com.la...5-2257/suppmat) shows the deviation from these null-distributions for each chromosomal arm. From this analysis we can draw two important conclusions: (i) it seems that for all chromosomal arms with >50 probed genes, a per patient summary of gene expression is in fact relevant since the spread in the estimate across patients is significantly higher than expected. This suggests that the added effects of chromosomal aberrations, other epigenetic regulation, and clustering of genes with similar transcriptional regulation significantly affects a majority of chromosomal arms; (ii) ranking of chromosomal arms according to deviation (z-score) from the corresponding null-distribution achieves an obvious similarity with a ranking based on frequency of chromosomal aberrations. Rennstam et al. ([2003]) report from a recent CGH experiment conducted on a cohort of 305 primary invasive breast cancers that gene copy number aberrations were observed in >90% of tumors, that all chromosomal arms were involved at various frequencies, and that the most common were: +1q (55%), +8q (41%), +16p (40%), +17q (28%), -13q (27%), -16q (22%), +20q (19%), -8p (18%), +11q (16%). The overlap in top ranking arms between Rennstam's et al. report and Supplementary Table 4 is consistent with previous reports that chromosomal aberrations are a major reason for the apparent genomic clustering of similarly expressed genes in breast and several other cancers (Phillips et al., [2005]; Fujii et al., [2002]; Aggarwal et al., [2005]; Reyal et al., [2005]). It is therefore reasonable to consider known chromosomal aberrations in 16q. Loss of heterozygosity in this arm is one of the most frequent events in breast cancer. E-cadherin is likely to be the tumor suppressor gene explaining recurrent loss of 16q in lobular breast cancers (Berx et al., [1995]). In search for the target gene in ductal carcinomas (comprising the majority of breast cancers) the smallest region of overlap (SRO) with regards to copy number aberrations has been exhaustively searched for. Several SROs have been suggested, but no clear consensus has been reached (Rakha et al., [2006]). Several putative genes have been screened and thus far none has fulfilled the criteria for target genes. Although the culprit gene seems elusive, 16q has been implicated in relation to important tumor characteristics. Loss of genomic material in 16q has been proposed an early event in a low grade-good prognosis pathway of breast cancer progression. In a CGH experiment, where invasive ductal Grade I and III breast carcinomas were contrasted, Roylance et al. ([1999]) found that 65% of Grade I tumors had lost the long arm of chromosome 16 compared with only 16% of Grade III tumors. This pattern of loss led the investigators to conclude that the majority of Grade I tumors do not progress to Grade III tumors, since it would be necessary for the Grade I tumors to regain lost material in 16q in order for this to happen. That at least two different genetic pathways for tumor progression exist for invasive ductal carcinomas (comprising the majority of breast carcinomas), and that loss of 16q is a key cytogenetic event, is further supported by Buerger et al., ([2001]). In Table 1, the same relationship between grade and 16q expression can be observed: tumors with high expression in 16q are more frequently high grade tumors and the inverse is true for tumors with low expression in 16q. Stratification of the 16q expression estimate across patient cohorts and histological grade demonstrated that 16q expression is generally higher in the Uppsala patient cohort, despite a smaller percentage of Grade 3 tumors (Supplementary Table 3; Supplementary material for this article can be found at http://www.interscience.wiley.com.la...-2257/suppmat). This systematic difference is unlikely to be biological in origin; when the cohorts are considered independently the same relationship between grade and 16q expression is obvious. The Grade 3 tumors have the highest and most distinguished 16q expression in both cohorts. As the mean expression in 16q has overlapping confidence intervals between Grade 1 and 2 tumors, it is reasonable to test the ability for 16q gene expression to discriminate between Grade 3 tumors on one hand, and Grade 1 and 2 tumors on the other (Supplementary Fig. 3; Supplementary material for this article can be found at http://www.interscience.wiley.com.la...-2257/suppmat). The ROC of this analysis is 0.72, which is slightly worse than the ability to discriminate between Sørlie subtypes. This is interesting when considering the studies of Roylance et al., ([1999]) and Buerger et al., ([2001]), where grade seems to be the most important feature with regards to the tumor profile of chromosomal gains and losses. Our analysis suggests that the expression-based classification of Sørlie et al. ([2001], [2003]) agrees better with 16q expression than stratification according to grade does. Obviously, it is important to keep in mind that we have used different methods; Roylance et al. ([1999]) and Buerger et al. ([2001]) have assessed DNA in relation to chromosomal position, we have assessed RNA.

The idea that the unique position held by 16q in relation to survival is a reflection of recurrent loss of 16q in a favorable prognosis pathway of tumor progression is intriguing, when expression in 16q across the Sørlie et al. breast cancer subtypes is considered. Expression in 16q across the Sørlie et al. tumor subtypes, as reproduced in the current data set, indicate that they should be grouped into a high and a low expression group. The high expression group consists of basal, ERBB2, and luminal B subtypes, the low expression group of luminal A and normal-like subtypes. It is interesting that separating the patients in two groups, based on expression in 16q, produces a better agreement with the Sørlie et al. breast cancer classification than with the division of patients into poor and favorable prognosis categories. A possible explanation for this would be that the 16q and Sørlie et al. classifications are more direct descriptions of the biology of the tumor. Survival has a more complex relationship to tumor biology, and is affected by potentially tumor independent factors, such as treatment. Given the proposed model of tumor progression, expression in 16q across the Sørlie et al. subtypes would suggest that the ERBB2, basal, and luminal B tumors progress along the high grade-poor prognosis path, while luminal A and normal-like tumors progress along the low grade-good prognosis path. The identification of a possibly pivotal gene expression difference in 16q between luminal type A and luminal type B tumors is unexpected. The luminal type B designation does, however, seem to identify a group of tumors with poor prognosis and, in contrast to what is expected for the poor prognosis pathway, a quite high frequency of ER receptor expression. Recently, Roylance et al. ([2006]) have published a paper, describing results of an array-CGH experiment focusing on 16q. They now interpret their data as being more consistent with a significant number of ductal carcinomas progressing through grades, with subsequent accumulation of segmental gains on 16q in the higher grade lesions. Our findings do not contradict this, but a no less interesting questions is raised: have ERBB2, basal, and luminal B subtypes often progressed further along this proposed common path, explaining why they frequently have high expression in 16q, or is increasing 16q expression in fact accompanied by a phenotype shift from luminal A and normal-like subtypes to the others? Additional experiments are of course necessary to elucidate this.

The fundamental aim of this study was to test if specific chromosomal positions - implicated by a possible influence on gene expression - could be connected to useful clinical endpoints, and to investigate if the result would reflect previous findings regarding chromosomal aberrations in breast cancer. Regarding 16q, our data on gene expression are consistent with previous findings on copy number aberrations in this region, as discussed. Corrected P values were significant for a few other chromosomal arms also: 20q, 1p, 13q, and 9p. In 20q multiple regions - among them 20q11 - have been found to be recurrently amplified in breast cancer (Kallioniemi et al., [1994]; Hodgson et al., [2003]), and amplification in at least one region has been associated with a significantly shorter disease-free survival (Tanner et al., [1995]). Loss of heterozygosity in 1p has been reported in a large number of human cancers, including breast cancer, where association with reduced patient survival has been demonstrated (Ragnarsson et al., [1999]). The long arm of chromosome 13 harbors two well-known tumor suppressor genes, RB1 (13q14) and BRCA2 (13q12-13), the latter involved in hereditary breast cancer. In sporadic breast cancer LOH in several 13q regions - 13q12-13, 13q14, 13q21-22, and 13q31-q34 - is recurrent (Eiriksdottir et al., [1998]; Tong et al., [2004]), and for 13q12-13 it has been associated with a 3- to 4-fold increased risk of relapse and death (Eiriksdottiret al., [1998]). In 9p, loss of heterozygosity is frequent and has been associated with more rapid cell division and aneuploidy, although no significant association with survival was apparent (Eiriksdottir et al., [1995]). The expected effects on gene expression of these described gene dosage alterations are all consistent with our findings.

So, we may conclude that the chromosomal positions overrepresented in relation to survival largely reflect published data on recurrent chromosomal aberrations. For researchers dealing with expression data in cancer this is an important issue since physical genomic clustering of genes with similar transcription is not confined to tumor tissues; it has previously been described in yeast and normal tissues of mice and human (Cohen et al., [2000]; Hughes et al., [2000]; Su et al., [2004]). In cells or tissues, where euploidy can be expected, epigenetic mechanisms of gene regulation and clustering of functionally related genes are believed to be the cause. Although direct examinations of the effect of gene copy number aberrations on gene expression has been described as substantial (Hyman et al., [2002]; Pollack et al., [2002]; Linn et al., [2003]; Wolf et al., [2004]; Aggarwal et al., [2005]; Bea et al., [2005]; Grade et al., [2006]), the inverse is not necessarily true; clustering of functionally related genes or epigenetic mechanisms of gene regulation could be the major cause for disproportionate contributions from certain genomic regions to differential gene expression in cancer also.

In conclusion, our results indicate that important biological information can be extracted from gene expression data in breast cancer by studying non-random connections between chromosomal positions and gene expression. We feel that investigation of a possible influence of specific chromosomal positions on gene expression in tumors should be attempted more often. When Sørlie and coworkers first classified breast tumors based on pervasive gene expression differences (Perou et al., [2000]), a group of breast cancers characterized by few chromosomal aberrations but recurrent loss of 16q had been described a decade earlier (Dutrillaux et al., [1990]). Our data strongly indicate that this described group of tumors significantly overlaps with the luminal A and normal-like subtypes, illustrating how novel gene expression-based descriptions of tumor biology can find additional support by using the extensive amount of published data regarding chromosomal aberrations available in cancer. It is likely that additional chromosomal positions can be implicated in relation to other clinical variables, or in relation to results from any of the many bioinformatics tools available for analysis of gene expression data. This holds promise of pinpointing chromosomal regions - or even individual genes - pivotal in activating or suppressing pathways, transcriptional networks and other gene expression themes important for various aspects of tumor biology.

[Lani]

Title: Gene expression in 16q is associated with survival and differs between S?rlie breast cancer subtypes.
Source: Genes, chromosomes & cancer [1045-2257] Wennmalm yr:2006

[karenann]

Lani,

I don't really understand this information. Is there some way your can explain the study? I would really appreciate it. I actually thought I was starting to understand these articles, but I guess not.

Thanks,

Karen

[Hopeful]

Karenann, I am with you in needing some help here. This is what I got out of it:

The investigators were examing the relationship of chromosome position and gene expression relative to recurrence and survival in breast cancer. They divided bc patients into 4 subtypes, one of which is Her2+/ER- and another Her2+/ER+. They found that loss of expression in chromosome 16q was inversely related to survival in IDC bc. They postulate that loss of 16q expression is a truer reflection of tumor grade than observation of the tumor. They found that loss of 16q was associated with low grade, good prognosis bc and the higher the 16q expression, the higher the grade and the worse prognosis. They believe this demonstrates multiple pathways for bc progression, and that there is not necessarily a linear progression from low grade to high grade. Their explanation for this was that 16q loss often extended to the entire arm of the chromasome, and, in order for a low grade tumor to become a high grade tumor, it would have to recover some of the lost chromasome 16q. Both the Her2+/ER- and Her2+/ER+ tumors retained more 16q expression than the lower grade tumors, with corresponding worse prognosis for recurrence and survival.

Lani, how did I do?

Hopeful

[Hopeful]

I went searching on the web and found the abstract for Lani's article:

Research Article
Gene expression in 16q is associated with survival and differs between Sørlie breast cancer subtypes

Kristian Wennmalm 1 *, Stefano Calza 2, Alexander Ploner 2, Per Hall 2, Judith Bjöhle 1, Sigrid Klaar 1, Johanna Smeds 1, Yudi Pawitan 2, Jonas Bergh 11Department of Oncology and Pathology, Cancer Center Karolinska, Radiumhemmet, Karolinska Institutet and University Hospital, Stockholm, Sweden
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
email: Kristian Wennmalm (Kristian.Wennmalm@cgb.ki.se)
*Correspondence to Kristian Wennmalm, Cancer Center Karolinska R 8:3, Karolinska Institutet and University Hospital, S-171 76 Stockholm, Sweden

setDOI("ADOI=10.1002/gcc.20392")Funded by:
Swedish Cancer Society
Research Funds at Radiumhemmet
The Swedish Research Council



AbstractWe have investigated the relationship between gene expression and chromosomal positions in 402 breast cancer patients. Using an overrepresentation approach based on Fisher's exact test, we identified disproportionate contributions of specific chromosomal positions to genes associated with survival. Our major finding is that the gene expression in the long arm of chromosome 16 stands out in its relationship to survival. This arm contributes 36 (18%) and 55 (11%) genes to lists negatively associated with recurrence-free survival (set to sizes 200 and 500). This is a highly disproportionate contribution from the 313 (2%) genes in this arm represented on the used Affymetrix U133A and B microarray platforms (Bonferroni corrected Fisher test: P < 2.2 × 10-16). We also demonstrate differential expression in 16q across tumor subtypes, which suggests that the ERBB2, basal, and luminal B tumors progress along a high grade-poor prognosis path, while luminal A and normal-like tumors progress along a low grade-good prognosis path, in accordance with a previously proposed model of tumor progression. We conclude that important biological information can be extracted from gene expression data in breast cancer by studying non-random connections between chromosomal positions and gene expression. This article contains Supplementary Material available at http://www.interscience.wiley.com/jp...5-2257/suppmat. © 2006 Wiley-Liss, Inc.Received: 9 June 2006; Accepted: 18 September 2006

Hope this helps - Hopeful

[Lani]

In addition:They postulated there are two main sequences/pathways that breast cancer follow in developing more and more mutations which make cells more and more immortal and proliferative--one which the normal and luminal A take (ER+her2-) with lots of chromosome 16q loss and associated with good prognosis and one which basal(triple negative) ERBB2 (her2+er-) and luminal B (some, but not all, of which are her2+ER+) which are not associated with lots of chromosome 16q deletion and have a worse prognosis. Interestingly they seemed to use ER of 2% as the cut-off for ER+ so their percentage ER positive comes out interestingly for basals and ERBB2s. As we have pointed out before, there are many ways to measure ER and not all are accurate nor do they necessarily concur with each other.

I was interested to see that they found a shorter DFS for her2+s than for basals. This was not a huge study, but opens the way for larger studies.

They will have to go further back in their archive of tumors(may not be easy because, althought they did not say it outright in the original article, it sounded like they used fresh tumor or fresh frozen tumor rather than paraffin embedded tumor to do their studies) to get the results of DFS without tam tx, without AI tx, without chemotherapy, with and without herceptin for us to discover not only the natural history, but also the results of different treatments on these tumors.

Hope this article elucidated more than it confused!

[Hopeful]

Lani, this is a fascinating article, and thanks for posting it. I was a bit thrown by the fact that there were ER-'s with + percentages of ER; I didn't get the 2% cut-off point. What is disheartening is that they state the information on 16q has been around since 1990, and doesn't appear to have been further investigated.

One question I have on your last post is about the Luminal B group: Is this all Her2+/ER+ and some others, or some Her2+/ER+ and some others? If the latter, how is it determined? Does PR enter into it?

Thanks for all you do,

Hopeful

[Lani]

egorization of breast cancer, it includes all ER+her2+ breast cancers and some others ie, all strongly ER+her2+ bc falls in this category. I will work on reading the original article to understand this 2% categorization better if I can.
From what I understand her2neu is on chromosome 17...this article is the first I read on chromosome 16.
The other article is hot-off-the press today as wel is fascinating and has to do with chromosome 17. It is by Martine Piccart , the head of all the HERA trials, among others and is on how best to test for those her2+ patients who will most likely respond to herceptin ie, IHC vs FISH correcting for an aberrancy of chromosome 17 which creates a false positive. It concluded that those whose FISH was >6 did not suffer from this aberrancy which could create the false impression of her2 overexpression.

As I remain crummy at adding things to posts without losing them, I will add the reference as my next reply to this thread.

[Lani]

: Mol Cancer Ther. 2006 Oct;5(10):2572-9. Links
Correction for chromosome-17 is critical for the determination of true Her-2/neu gene amplification status in breast cancer.

Dal Lago L,
Durbecq V,
Desmedt C,
Salgado R,
Verjat T,
Lespagnard L,
Ma Y,
Veys I,
Di Leo A,
Sotiriou C,
Piccart M,
Larsimont D.
Department of Pathology, Jules Bordet Institute 1, rue Heger-Bordet, 1000 Brussels, Belgium. denis.larsimont@bordet.be.
Purpose: Trastuzumab is the cornerstone for treatment of women with HER2-overexpressing breast cancer, both in the adjuvant and in the metastatic settings. The accurate assessment of HER2 is, therefore, critical to identifying patients who may benefit from trastuzumab-based therapy. This project aimed to determine the optimal scoring method for fluorescence in situ hybridization (FISH) assay. Methods: FISH assay was done on 893 samples of breast cancer. Three scoring methods were evaluated: Her2/CEP17>/=2, Her2>4, or Her2>6. Protein and gene expression were evaluated by immunohistochemistry (n = 584) and mRNA/assay/nucleic acid sequence-based amplification (NASBA; n = 90). Results: Samples were divided into five groups based on FISH results: disomic amplified and nonamplified, polysomic amplified, nonamplified, and discordant (10.8% of cases, mostly positive with Her2>4 scoring, but negative with the others). Her2/CEP17>/=2 and Her2>6 scoring methods showed the best association (a) with regard to FISH scoring (kappa = 0.906, P < 10(-6)) and (b) between FISH and immunohistochemistry (3+ as positive; kappa > 0.650, P < 10(-6)) or NASBA (kappa > 0.536, P < 10(-6)). Polysomy had an effect on Her2 copy number (P < 10(-6)), but had no effect on protein and mRNA content. Therefore, within the discordant subgroup, for which additive Her-2 gene copies are due to high polysomy, protein and mRNA levels were similar to those of the nonamplified samples. For this subgroup, the best concordance between FISH/immunohistochemistry/NASBA was observed with the Her2/CEP17 ratio and Her-2>6 scoring (68% and 58% perfect matches, respectively). No perfect matches were observed using the Her2>4 scoring method. Conclusion: Correction for chromosome-17 is the method of choice for clinical practice; Her-2>6, but not Her-2>4, could be used as an alternative. [Mol Cancer Ther 2006;5(10):2572-9].
PMID: 17041102 [PubMed - in process]

[Hopeful]

Lani, Here is a link to the article by Sorlie referred to in the article you posted about 16q: http://www.pnas.org/cgi/content/full/98/19/10869 This was one of the earlier articles I read about gene patterns and bc. I am still a bit confused by their classification of Luminal B and Luminal C; they seem to lump them together sometimes, and other times distinguish them as separate groups. It also shows the Luminal B's bouncing around on the graphs where they do their gene groupings. If you have an interpretation of this characterization, I would be most interested in reading it, as you seem to have an excellent grasp on all of the molecular biology issues.

thanks,

Hopeful