Types of chemo tx, neo-adj vs. adj. etc

[Val Pfeiffer]

I was surfing around this site tonight and I happened to read Kate's signature line -- many of us list the facts about our case, and Kate had listed her neo-adjuvant chemo, which was 4 A/C and 4 taxatore, and this was her treatment very recently, one year after my treatment regime.

Here is my question: what is considered the "gold standard" with regard to chemo tx for Her2+++ breast cancer? When I received the combination of Taxol, Carboplatin and Herceptin for three months prior to my mastectomy and the same drugs for three months after surgery, it was my understanding that was the best approach for this type of cancer. Yet women are still getting A/C and Taxatore. Does anyone know why this is the case? Maybe I was misinformed in December 2004 when I started my treatment.

I find the differences in treatment approaches frustrating at times; I met a woman who had a very similar case as mine, and her oncologist practices in the same group as mine does. Yet she had surgery first, rather than three months of neoadjuvent chemo, which produced such dramatic results in my case.

This certainly isn't an urgent question, but since recurrence is so likely in Her2 cases, I want to get this answer...someday I may need it!

Val

[Lani]

It is unlikely that your tumor is the same size, has the same amount of (if any) lymphvascular invasion, has the same ER%or PR% , the same Ki-67value, has the same amount and degree of lymph node involvement, that you are in the same state of pre/peri/or post menopause, that you have the same medical problems (liver failure, history of hepatitis C, neurological disease, heart disease) or have the same wishes than another person. And there is not yet one RIGHT way to treat this disease...every year the Europeans and the North
Americans (it may not be as often for the No. Americans I will have to go back and look ) try to publish a consensus OPINION on how to treat different patients but it is A WORK IN PROGRESS.

Some oncologists hear reports at major meetings and start to change their practices before it becomes common practice(or even is entirely validated). At San Antonio last December , Dr. Slamon presented early results of a study showing the her2 and topoIIa tend to be coamplified (they sit near each other on the same chromosome and the error which causes her2 to be copied over and over again like a broken record can also cause the nearby topoIIa to be copied over and over again)

[Lani]

Their paper hypothesized that when this was the case Anthracyclines would
be more effectively combined with herceptin than when this was not the case and proposed that IF THIS PROVED OUT IN THE LONG-RUN that perhaps one could save thousands of patients the toxicity of anthracyclines and markedly reduce the cardiotoxicity of herceptin (as it seems to be the combination of the anthracycline caused damage and the herceptin caused damage which causes most cases of herceptin-induced cardiotoxicity)

Dr. Slamon gave a preliminary report on a relatively small number of patients treated with TCH instead of A/C T and H which showed survival benefit of approximately 42-45% instead of 50% (numbers not exact, but not far off) compared to chemotherapy alone. Again, he proposed that if these numbers continued to show
similar results as the study matured that perhaps TOPO IIa testing MIGHT BECOME the new standard of care, with those testing negative for TOPO IIa PERHAPS receiving TCH, with anthracyclines(ie A/C+TH) reserved for those who were TOPO IIa positive.

Since San Antonio I have read two papers, from other groups stating that topoIIa positivity is not always associated with anthracycline efficacy. Perhaps the story is not so simple or perhaps their study was done in some different way or their patients tended to have different tumor subtypes than Dr. Slamon's. It appears there are different types of her2+ tumors besides the ER+PR+, ER+PR- and ER-PR-.

I think some oncologists went home from San Antonio thinking this WOULD
become the new standard of care. Since all those being treated off protocol with adjuvant and neoadjuvant herceptin for early breast cancer are still being treated with a drug which has not been FDA approved for the purpose, oncologists feel they can have some leeway in how they treat any individual patient.

Neoadjuvant chemotherapy is in general as I understand it only offered to those with larger tumors in order to allow them to have breast conserving surgery instead of a mastectomy. This allows one to tell if the treatment is working or not
(change in the tumor by exam, US, MRI, PET/CT,etc). Some patients are now getting neoadjuvant hormonal therapy in clinical trials.

Having recently helped an 84 year old with her2+ breast cancer with information on which to base her decisions I can say that it is a good thing that there is no one way to treat all her2+ breast cancers. Would you want chemotherapy as an 84 year old?

[Lani]

Hope this helped!

[tousled1]

Val,

I don't know why my oncologist chose the neo-adjunct chemo that she did. At that time I was very uninformed and still in a state of shock. I just went along with what she decided. The only thing I knew was that I did not want surgery first -- too close to the Holidays (stupid reasoning??). I can tell you that my onc did state that with the A/C and then Taxatore there was good results in tumor shrinkage. I can attest to that -- the tumor did indeed shrink but I still opted for the bilateral mastectomy. I didn't want to have to go through surgery again if I had recurrence. Another factor may be that I was 57 at the time of my diagnosis and we already knew that there was lymph node involvement. I had lymph node needle aspiration biopsy done at time of initial biopsy. Other factors that were unfavorable in my biopsy report were Ploidy/DNA index (Aneuploid/1.61) and S-phase 24.2%. Like Lani said, it's like comparing apples and oranges. The most important thing in any treatment plan is the end result.

[Val Pfeiffer]

Thanks, Lani and Kate. I certainly understand that each patient is completely different. I still can't help but wonder about using Herceptin vs. not using Herceptin with chemo... why it is chosen for some Her2 cases and not for others. The adjuvant vs. neoadjuvant is an entirely different topic (in which I am also very interested). I know there aren't any exact answers to this, but I find this topic fascinating. I am looking more for debate and discussion with this thread than answers :-)

Val

[CPA]

Herceptin is NOT used with A/C because it causes a large number of people to lose cardiac function (this is why people get MUGA or echo tests fairly regularly when taking Herceptin). It was found that waiting to finish A/C then starting H decreased - but did not always completely eliminate - the impact on heart muscle. Carboplatin and Taxanes are relatively safe when used in conjunction with H so they are taken at the same time.

[Val Pfeiffer]

I need to re-state my question--my communication skills are not too great today! I understand why A/C and Herceptin aren't used together. I want to know under what circumstances A/C is still being used instead of Herceptin for Her2 cases.

[Alice]

Hi Val,

I don,t have the answer to your question. I had 4 A/C dose dense then 12 weeks of carbo/taxol/herceptin as neo-adjuvant. I was part of a study as this was not the usual protocal at the time. I'm not sure that even the experts can answer this one. I'll keep an eye on this post as It may come in handy.

Alice

[Becky]

AC is not used instead of Herceptin. Usual protocol if using AC is AC followed by taxane with Herceptin then Herceptin alone until one yr of Herceptin has been used. In small tumors with no nodes involved, AC is used then followed by a year of Herceptin. Some oncologist who use AC like the AC followed by a taxane followed by Herceptin (not combining).


It is hard to say what the gold standard is. Adriamycin (the A in AC) or epirubicin (another anthracycline that is like Adriamycin) are used traditionally if one is Her2+ because Her2+ disease responses well to an anthracyclin. Current thinking now is that it is really being TopoIIA+ that is the responder to an anthracyclin but TopoIIA is strongly associated with Her2+ (about 57% of Her2+ cases are also TopoIIA+ as well). So, if you don't or can't get your tumor tested for TopoIIA, then one should take the anthracyclin based therapy (AC followed by perhaps a taxane and herceptin), because if you are topoIIA+, the bc responds well to the anthracyclin. If you are lucky enough to get tested, and are topoIIA negative, then TCH is good as it works very well and is easier on the heart.

I may come up with more later.

Kind regards

Becky

[Lani]

which shows that many "facts and widely accepted truisms" are subject to alteration as more information becomes available. Which "fact" turns out to be valid is still to be seen as this process evolves:
ABSTRACT: Predictive value of HER-2 and Topoisomerase II? in response to primary doxorubicin in breast cancer [European Journal of Cancer]
Aim: To study the predictive role of HER-2 and Topoisomerase II? (TOP2A) in response to primary doxorubicin.

Methods: Two hundred and thirty-two patients with operable breast cancer were treated with doxorubicin prior to surgery. ER, PgR, grade, Ki-67 and HER-2 status were prospectively assessed. HER-2 overexpression was evaluated with immunohistochemistry; positive cases were then studied for gene copy number of HER-2, TOP2A and chromosome 17 centromere by chromogenic in situ hybridisation. Clinical response was assessed by mammography. Pathological response was evaluated as the percentage of tumour replaced by changes due to chemotherapy.

Results: HER-2 amplification was associated with clinical response (p = 0.04). ER and PgR negativity, high Ki-67 and HER-2 amplification significantly correlated to pathological response (p < 0.05). Tumours with coamplification of HER-2 and TOP2A showed a higher percentage of pathological changes (p = 0.6). However, in the multivariate analysis for complete pathological response, ER negativity and high Ki-67 index were the only parameters that maintained statistical significance.

Conclusion: HER2 and Topoisomerase II? amplification failed to show an association with pathological response to doxorubicin, whereas ER negativity and a high proliferation rate were predictive of complete pathological response to this regime.

So it might not be so simple...

[Mary Anne in TX]

It has helped to hear the answers to your question! I had Adriamycin and Taxotere before my surgery (it didn't work) but I'm so glad we tried!!!! Then after my mas plus 7 of 9 positive nodes, I had Carboplatin, Taxol, and Herceptin. Now am doing Navelbine and Herceptin (so excited, just 3 more to go)! Then radiation & Herceptin and then Herceptin through June!

I've been curious about how what I am doing compares to what others have done! I really appreciated your question and the information given by those who answered you!

Thanks to all,
Mary Anne

[Lani]

ABSTRACT: Molecular subtypes of breast cancer and amplification of topoisomerase II?: predictive role in dose intensive adjuvant chemotherapy [British Journal of Cancer; Subscribe; Sample]
Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II? (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.
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