The amount and quality of work you have been doing for us is absolutely breathtaking, especially on the eveof your treatment program. We all wish you successful chemotherapy and our prayers are with you.
There is one important thing that I would like to add to your important summary-
You summarized “TNBC defined by IHC:the absence/low expression of ER, PR, HER2” and that is exactly the case throughout most of the country BUT Dr. Michael Press, a wonderful pathologist at USC, did a study and found that around 15% of the time IHC showed HER2neu to be negative when in fact it was positive. This is extremely important because if HER2neu+ Herceptin can be used.
The standard of care at many major cancer centers across the country is to utilize FISH tecnology in addition to IHC to measure HER2neu.
I think it is extremely important for the women in our marvelous family to ask for FISH to be done on their tumors.
Lee, please do not take my words as criticism in anyway...Just something that I feel, strongly, should be mentioned in your excellent overview.
again, my prayers are with you and shall be..good luck next week.
warmly,
Steve
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
Steve, you are absolutely correct about using FISH to test for Her2. The current recommendation is if Her2 is 3+ and above it should be verified by FISH.
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer Arch Pathol Lab Med, 131:8-43, 2007
The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3 + (uniform, intense membrane staining of 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1 +, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.
There are several major cancer centers who use the FISH test, for all women with breast cancer, regarding HER2neu, no matter the IHC HER2 level and no matter that the guidelines are as you indicate.
I think the philosophy behind this is simple according to a pathologist who explained the rationale to me. “The implications of using Herceptin may be so important to a patient’s survival, that we just want to be as sure as possible that the HER2neu level is truly negative. FISH is back-up insurance, even in tissue samples that have been graded 3+ by IHC. We want to make sure that a mistake is not made by just relying on IHC."
all the best,
Steve
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
Clinical Notice for American Society of Clinical
Oncology-College of American Pathologists Guideline Recommendations on ER/PgR
and HER2 Testing in Breast Cancer
Laboratory compliance with the American Society of Clinical
Oncology/college of American Pathologists guidelines for human epidermal growth
factor receptor 2 testing: a College of American Pathologists survey of 757
laboratories
On false positives and false negatives by the different methods:
Comprehensive immunohistochemical analysis of Her-2/neu oncoprotein overexpression in breast cancer: HercepTest (Dako) for manual testing and Her-2/neuTest 4B5 (Ventana) for Ventana BenchMark automatic staining system with correlation to results of fluorescence in situ hybridization (FISH)
The last official ASCO issued guidelines was what was published in 2007. I suspect that there are inter-institution variations in how good their IHC and FISH assays are.
It seems to me the ASCO guidelines are mainly concerned with false positive IHC results. I do not know the false positive and false negative thresholds nationwide.
As indicated in the first article, it is not a closed issue, certainly more will be forthcoming.
Herceptin has significant side effects, notably toxicity for the heart. This is particularly common when herceptin is used with adriamycin or other anthracyclin drugs. The anthracyclins are first line agents for TNBC so this is a significant issue. It is not just that you want to be sure to avoid false negatives, but also that you have a true positive before acting on it clinically.
First of all, please understand I am trying to help clarify not be confrontational on this topic. My main source on this topic is Dr. Michael Press who is one of the country’s leading pathologists. I attended a presentation he made a few years ago and have had the opportunity to speak to him several times. As an aside, besides being an outstanding pathologist he is co-director of USC’s Women’s Cancer Program and in my personal opinion a caring physician and a lovely man.
Conclusions: Compared with the HER-2 status determined at centralized BCIRG
reference laboratories, these results indicate superiority of FISH to
accurately and reproducibly assess tumors for the HER-2 alteration at
outside/local laboratories for entry to clinical trials.
This paper was written in 2005. At that time Dr. Press’s lab at USC was one of the few in the country, along with Mayo Clinic that was doing FISH. Now, it is my understanding, several more major cancer centers do FISH testing and as I mentioned in my original post several of them do it, no matter the IHC results.
As recently as a few months ago, an oncologist I know well told me he was sending the patient’s tissue out to Mike Press’s lab at USC because “I think he is the best.”
Lee, I am not saying that any of your references are incorrect; just that there are different perspectives on this. I personally feel the major cancer centers who are doing FISH testing on all breast tumors are correct.
........
David, I agree with you entirely. It is clear that, for some women, there can be serious cardio-toxicity issues with Herceptin. At the same time, Herceptin, it seems, in many cases, helps women with HER2+ breast cancer survive. One of the key topics discussed at SABCS a few months ago was Herceptin and also the use of other experimental drugs with Herceptin in clinical trials, sometimes with superior results, at least preliminarily.
..............................
Perhaps to better understand my views I would also like to express them on Memorial Sloan-Kettering Cancer Center’s (MSKCC) recent policy (about two years ago) of recommending that ALL women who have had surgery, at MSKCC, for ovarian cancer be recommended to meet with a Certified Genetic Counselor to discuss testing for the BRCA mutation, even absent any family history of breast/ovarian cancer. Certainly their program is not currently endorsed by the major medical bodies and can be quite expensive to administer but I know they have found women with the BRCA mutation which would not normally have been found, and that knowledge may affect the treatment these women are having, and also this knowledge is important regarding the breast cancer risk these women have, as a separate risk to ovarian cancer.
The numbers may be relatively small, to some, in the case of FISH testing and in the genetic testing at MSKCC but I believe lives are potentially being saved because of it and I still feel, as is written, “to save one life is to save mankind.” Perhaps some feel I am being overly-dramatic but I think that is what is involved in both cases. I personally don’t think that 5, 10 or 15% is an insignificant number.
warmly,
Steve
Edited by steve - Jan 27 2012 at 11:23am
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
From a purely technical perspective, the fluorescent dyes have many attractive features. Beginning with the assumption that computers are intrinsically dumb (I know, I work with them ;), it is much easier to write. A program to automatically score fluorescently labeled slides than it is to score immunohistochemistry. To be honest, I am surprised that FISH has not replaced IHC in most applications. But that is only technical issue. Really need the clinical data to make clinical decisions.
not surprisingly, I think breastcancer.org says it much better than I.
Steve
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
No offense taken at all. I post these article links for a number of reasons: 1) share what I have learned with the community 2) stimulate discussion 3) promote our advocacy with our docs in areas that we may not have been paying attention to.
I think you brought up a good question regarding Her2 testing, one that affects all of us. In my case I will be asking my oncologist on Monday about retesting using FISH. You might want to look at the first article from JNCI -- it cites Drs Press and Perez on the Her2 testing issue. As mentioned, IHC is more subjective and operator dependent -- this applies to both hormone receptor testing, Her2 testing and all other IHC based assays.
It is always good to remember that although test results come back in black and white so to speak, in reality, these are biological assays with their attendant technical considerations.
A recent basic science study showed that PTPn12 is inactivated in some TNBCs (see Donna's post). Consequently, multiple kinase targets are activated. The authors suggested that using a multiple kinase targeting approach with sunitinib and lapatinib would be helpful. I looked for what is known about these drugs in clinical trials.
Conclusion:
1) these two drugs have not been used in combination in any subtype
2) most studies involving either of these drugs have not focused specifically on TNBC
3) sunitinib has not be shown to have efficacy in the settings tested
4) lapatinib is efficacious in Her2+ disease in the metastatic setting and in combination with herceptin in Her2+ early BC
Sunitinib, a
multi-target tyrosine kinase inhibitor
mostly in advanced BC
Sunitinib plus paclitaxel versus
bevacizumab plus paclitaxel for first-line treatment of patients with advanced
breast cancer: a phase III, randomized, open-label trial (2011)
Lapatinib versus trastuzumab in combination with neoadjuvant
anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 4): a randomized
phase 3 trial (2012)
Sunitinib plus paclitaxel versus
bevacizumab plus paclitaxel for first-line treatment of patients with advanced
breast cancer: a phase III, randomized, open-label trial (2011)
I don't really understand all that you are talking about but i know my post surgical pathology (mastectomy before chemo) report states that my tumor had the IHC analysis done and was sent for FISH analysis too. I just assumed this was a normal thing to do - my surgery was done at a local hospital connected with Moffitt - although my surgeon received a lot of his education from the University of Miami.
Blair
Lump found 11/08 DX: 2/09 @52 TNBC L. Mast. 3/26/09, SN-, BRCA-, 4.5 cm (post surgical)T2NOMO Chemo: 4/09-10/09 Taxol x 12, A/C x 4, No rad.No recon. NED 1/17. New Primary right breast TN, 2/2018.
Blair If your results from the two tests agree, and I assume they agree since you haven't heard anything to the contrary, then there is nothing to worry about. It's just that there are false positives and false negatives with all the tests and one would like to be sure about the results. Lee
Thanks for the information - i'm assuming they are both tests to confirm Her2+ or - status? Is that correct?
Thanks,
Blair
Edited by cheeks - Jan 27 2012 at 8:47pm
Lump found 11/08 DX: 2/09 @52 TNBC L. Mast. 3/26/09, SN-, BRCA-, 4.5 cm (post surgical)T2NOMO Chemo: 4/09-10/09 Taxol x 12, A/C x 4, No rad.No recon. NED 1/17. New Primary right breast TN, 2/2018.
Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer.
Nilsson G, Holmberg L, Garmo H, Duvernoy O, Sjögren I, Lagerqvist B, Blomqvist C.
Greger Nilsson, Lars Holmberg, Hans Garmo, Olov Duvernoy, Bo Lagerqvist, and Carl Blomqvist, Uppsala University, University Hospital, Uppsala; Iwar Sjögren, Falun Hospital, Falun, Sweden; and Lars Holmberg and Hans Garmo, King's College London, School of Medicine, London, United Kingdom.
PURPOSE To study distribution of coronary artery stenosis among patients with breast cancer (BC) and to assess correlation between radiotherapy (RT) and location of stenosis. PATIENTS AND METHODS A Swedish BC cohort diagnosed from 1970 to 2003 was linked to registers of coronary angiography from 1990 to 2004, which yielded 199 patients. Stenoses of the coronary arteries were graded from 0 to 5, where 0 indicated a normal vessel and 5 indicated occlusion. Two hotspot areas for radiation were defined: proximal right coronary artery (prox RCA), mid and distal left anterior descending artery and distal diagonal (mdLAD + dD). RT regimens were categorized as high or low risk of irradiating the hotspot areas. Left breast/chest wall was considered high risk for mdLAD + dD; left internal mammary chain (IMC), high risk for prox RCA and mdLAD + dD from 1970 to 1995 and thereafter solely for mdLAD + dD; and right IMC, high risk for prox RCA. Other RT targets and no RT were considered low risk. Results were expressed in odds ratios (ORs) and 95% CIs. Results For irradiated left- versus right-sided BC, the OR for grade 3 to 5 stenosis in mdLAD + dD was 4.38 (95% CI, 1.64 to 11.7), and for grade 4 to 5 stenosis, the OR was 7.22 (95% CI, 1.64 to 31.8). For high-risk RT versus low-risk or no RT, the OR for grade 3 to 5 stenosis in hotspot areas was 1.90 (95% CI, 1.11 to 3.24). CONCLUSION An increase of stenosis in mdLAD + dD in irradiated left-sided BC and an association between high-risk RT and stenosis in hotspot areas for radiation indicate a direct link between radiation and location of coronary stenoses.
PMID: 22203772 [PubMed - as supplied by publisher]
2. Rational use of intensity-modulated radiation therapy: the importance of clinical outcome.
Abstract
During the last 2 decades, intensity-modulated radiation therapy (IMRT) became a standard technique despite its drawbacks of volume delineation, planning, robustness of delivery, challenging quality assurance, and cost as compared with non-IMRT. The theoretic advantages of IMRT dose distributions are generally accepted, but the clinical advantages remain debatable because of the lack of clinical assessment of the effort that is required to overshadow the disadvantages. Rational IMRT use requires a positive advantage/drawback balance. Only 5 randomized clinical trials (RCTs), 3 in the breast and 2 in the head and neck, which compare IMRT with non-IMRT (2-dimensional technique in four fifths of the trials), have been published (as of March 2011), and all had toxicity as the primary endpoint. More than 50 clinical trials compared results of IMRT-treated patients with a non-IMRT group, mostly historical controls. RCTs systematically showed a lower toxicity in IMRT-treated patients, and the non-RCTs confirmed these findings. Toxicity reduction, counterbalancing the drawbacks of IMRT, was convincing for breast and head and neck IMRT. For other tumor sites, the arguments favoring IMRT are weaker because of the inability to control bias outside the randomized setting. For anticancer efficacy endpoints, like survival, disease-specific survival, or locoregional control, the balance between advantages and drawbacks is fraught with uncertainties because of the absence of robust clinical data.
There may be some variation in the definitions of first, second and
third generation regimens from site to site, and the details matter.
For example, adriamycin/cyclophosphamide followed by a taxane is second
generation, but if given on a shorter cycle with more intensive growth
factor support ("Dose Dense") it is considered a third generation. NCI
has a qucik summary
Last year when I was getting several opinions regarding radiation treatment, IMRT was recommended for my situation. I believe the machine I had was called Tomotherapy IMRT. Because of the wide area being treated, they thought IMRT would be the best choice for me with mabye less side effects and damage? I guess only time will tell. I do know that it was about 2-3 times more expensive than normal radiation. However, I had no problem with insurance coverage. Where I was treated in St. Louis, the cancer facility had 2 machines out of the total 4 in the whole area (two other hospitals had one machine each). So I think because the technology is newer and the expense of the machines, not all facilities will have them.
New radiation therapy technique Patients
with head and neck cancers are benefiting from a cutting-edge radiation
technique called intensity modulated radiation therapy (IMRT). K.S.
Clifford Chao, M.D., and other radiologists at Siteman Cancer Center are
among the few researchers nationwide who are studying the use of IMRT.
As an emerging technique, IMRT precisely targets tumor cells while
sparing surrounding normal tissue. This means, for example, nerves to
the eyes and brain are less likely to receive unintended radiation
during treatment of cancer of the nasal passages. IMRT also means the
tumor gets a higher concentration of radiation than it would with
conventional techniques. Chao showed that IMRT minimizes damage to
salivary glands, sparing patients the long-term discomfort of dry mouth.
Patients receiving conventional radiation for head and neck cancers
often suffer from this side effect, which causes constant thirst and
inability to speak or eat normally. Chao is assistant professor of
radiology at the medical school's Department of Radiation Oncology.
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09) 11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15
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