Pattern of recurrence of early bc differs by intrinsic subtype & proliferation index

[Hopeful]

http://breast-cancer-research.com/content/pdf/bcr3559.pdf

Hopeful

['lizbeth]

Here you go Linn65:

Based on genomic-defined luminal tumors, it has been possible to establish a value of Ki-67 with prognostic utility and useful to distinguish between both classes of luminal tumors, A and B [12]. Moreover, several studies have confirmed the prognostic usefulness of these intrinsic subtypes defined by four [6-10] or six immunohistochemical markers [8,13-15].

However, it is not clear the value of Ki67 as a prognostic marker in the other intrinsic subtypes such as triple negative and HER2-enriched.

In our study, only the luminal population demonstrated significant differences in actuarial BCFS according to Ki-67 value.
No significant differences were found in triple negative and HER2-enriched tumors.

It is possible that these findings occurred because we use a Ki-67 cutoff
obtained in luminal tumors. Nevertheless, Aleskandarany et al. also failed to detect a significant difference in actuarial survival, despite using different cutoffs defined specifically for both triple negative and HER2-enriched tumors

This study shows that the KI-67 score might not be as big of a factor in Her2 positive cancers.

Only 25% of the patients had received a taxane, and only 18 patients in this analysis received Herceptin. Since the patient information is prior to 2009.

It is good information from a historical perspective. I can't wait to see how Herceptin has changed Her2 from what is so obviously the worst diagnosis to one of the luckier and more treatable breast cancer.

['lizbeth]

I'm still digging out nuggets from the article and found a couple more interesting pieces. The first is about Her2, margins & early recurrence:

The first peak of early relapses has been associated with surgery because the removal of the primary tumor could trigger the growth of clinically unapparent dormant micrometastatic foci[42].

Surgery could promote the growth of micrometastatic disease through several processes as an alteration in the angiogenic balance [42,43], surgical stress-induced neuroendocrine activation [44] or alteration of the immune response [45,46].

These mechanisms could influence particularly the disease course in intrinsic subtypes with a high expression of proliferation pathways such HER2 or basal-like tumors.

An increase of proliferation has been reported in HER2-positive patients with positive margins after conservative surgery between the first and the second tumor samples, as determined using Ki-67 immunohistochemistry; this was not the case with HER2-negative cases [47].

[Hopeful]

What I found interesting was this:

In addition, those other patients with Luminal-HER2 subtype could benefit from a second treatment with trastuzumab in order to decrease the second peak of recurrences.

I recall discussion here from way back, that perhaps triple positives could do with a "booster" of Herceptin at the 5 or 7 year mark.

Hopeful

['lizbeth]

This shows a novel shift in the management of preventing recurrence and not just treating intial cases or recurrences. The suggestion is to use Herceptin in the future to prevent many Her2 positive cancers that recur in the 5-6 year range.

The information provided from the study of the patterns of recurrence in early breast cancer would benefit to the patients in different ways. In this regard, our results could generate several hypotheses that, if confirmed in prospective randomized trials, would have noteworthy practical value. First of all, the surveillance after initial treatment could fit to the expected recurrence pattern depending on each intrinsic subtype. But more importantly, the adjuvant treatment could be tailored more accurately according to each intrinsic subtype.

Patients with tumors with high proliferation rate such HER2-enriched or basal-like would benefit from more aggressive chemotherapy schedules (e.g. dose-dense). Such type of chemotherapy could avoid some of the recurrences appeared during the first peak. Also in these cases with high expression of proliferation pathways, it could be especially useful the treatment with novel inhibitors of cell cycle (e.g. palbociclib).

In addition, those other patients with Luminal-HER2 subtype could benefit from a second treatment with trastuzumab in order to decrease the second peak of recurrences.

['lizbeth]

That is just too weird Hopeful. We are on the same page!

['lizbeth]

Has anyone done a clinical trial with the triple positives and a second round of Herceptin? I think prior to the 5 year mark, 48 to 50 months would be the safest strategy for prevention. (and I personally would want more than 1 booster, maybe 1 per month for 6 months.)

I also wonder what affect the E75 or AE37 vaccines are having on the late recurrence rates.

This is just such a change in thinking from the wait and see, and let a huge percentage of women recur. I would love changes to the standard of care.

['lizbeth]

Triple positive recur about the 5-6 year mark, isn't that about the time the 5 year treatment of Tamoxifen is up? This might also be a factor.

[SusanN]

WHEW Mister Sister...VERY, VERY INTERESTING...!!! I usually do try & read what is posted in some of these articles (when I have time...) just don't comment, what can I say, except that this information is beyond me...knowledge is power!! :)

['lizbeth]

I'm not fond of the wait & see, and try to find symptoms system of cancer surveillance. If we can find a way to prevent or some less invasive testing to screen survivors - I'm waving my pom poms!

[JennyB]

I wonder how many oncs/insurance companies would prescribe the booster shots though? I for one would love a top up in 18 months - would seriously pay out of pocket too - but would need the doc to go with my wish and probably some data!! Great topic though thank you xx

[Hopeful]

The "booster" would be easier, now that Herceptin is becoming available in forms other than infusion (i.e., subcutaneously). It would be less expensive than having to go to an infusion center. I do think that this would need to be tested before it becomes standard practice.

Hopeful

[Hopeful]

In re: booster, look here: http://her2support.org/vbulletin/showthread.php?p=224894&highlight=booster#post224894

Hopeful

[SusanN]

Hopeful & 'lizbeth, thank you so very much for extracting so much valuable information...as to "wait & see, symptoms...!!" I'm going to share this article with my oncologist, he always tells me IF I can find anything that would convince him, he would be willing to take a look at it...hmmm...(yeah, right?!?!)...

I find some articles of interest from "PracticeUpdate", Oncology Daily Digest...I'm sure others of you read that as well.

Kinda off the subject...very, much...anyhow, a year ago this month is when I found my "pea"...NOT from a mammogram or ultrasound...and today I go for my yearly mammogram, the only one I still have...trust me, I've called them already & explained "where I'm coming from..."...makes no difference as we know "dense breasts"...

Okay...didn't mean to go there...I'm with you JennyB...all over this "Booster"...it just may be adding up...hmmm...

['lizbeth]

I like the idea of the booster.

After looking at Hopeful's prior conversation I see perhaps two higher risk times, one about a 2-2 1/2 year interval, another at 5-6 years with ER+, Her2+.

I love the idea of the Herceptin injections as boosters. Do we really need a clinical trial? Almost all have had an entire year of Herceptin infusions. For stage 1-3 who remain as NED this has been for prevention. To receive an injection booster at 18 months, then 24 mths, 48 mths and 60 mths for ER+, Her2 patients should be something left to the discretion of the oncologist and patient.

"Modern" medicine will never achieve personalized care if the FDA has to approve & micromanage everything based on clinical trials for the good of the group, and not the individual.

[jaykay]

I'd do a booster in a heartbeat and I still have one more Herceptin to go (next Wednesday, Oct 30th).

But would it just be one "loading" dose or a couple of doses? I know there are no answers...

Susan - your mammograms now should be diagnostic vs. screening and you should get the results before you even leave the facility. Prescription should be written that way.

Best
Janis

[Laurel]

Smart People than I,

I am a bit confused by this study and think I must be reading it wrongly. Please, if anyone can, help me to wrap my brain around this. On page #14 in table #9 I see that the hazard ratio for recurrence in Luminal Her2 is actually declining annually through years 5-7. It appears that Her2 Enriched does spike around year 5, however. Isn't Luminal Her2 that which is Er or Pr (or both) positive and Her2 positive (Er/pr+, Her2 +) while Her2 Enriched is Her2 positive, but hormonally negative (Er/Pr-, Her2 +)? I must be reading that table wrongly because according to my interpretation Luminal Her2s would not require a booster, but Her2 Enriched would qualify.

Anyone?

['lizbeth]

Laurel,

We picked it up off of page 4 - from other studies:

Different authors have described the maximum peak of recurrence risk at 12-24 months after surgery [16-22] and the occurrence of a second peak at approximately the fifth year in some cases [17,18,20,22].

I did find the same confusion - about the terminology.

From prior reading I was under the impression that Her2 positive, hormone negative cancers recurred within the first 2 years then dropped. Recurrences with Her2 Positive ER Positive cancers had a tendency to occur more frequently beyond 2 years.

I think this brings us back to the prior discussion: Who is recurring? and the fact that SEERS does not track this type of data.

I will take another look . . .

['lizbeth]

Just so we understand for the purposes of this study Luminal Her2 is defined as:

Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR

from page 3

['lizbeth]

If you look at page 12 under: Analysis of recurrence prognostic factors and variations in recurrence risk over time
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Here they state for both Her2 populations there is a peak at 72 months and it was higher for the lower KI67 scores.

['lizbeth]

I think this conclusion is very important to preventing recurrence:



Our most important findings are that each intrinsic subtype displays a specific pattern of recurrence and that the proliferation pathway plays a key role in the development of early recurrences. These results directly point to adjuvant treatment approaches and clinical follow-up schedules for surveillance, suggesting that both should be different depending on intrinsic subtype.
It is fun to analyze these studies. But keep in mind there was a population of 151 women who were Her2 enriched and ONLY 18 received Herceptin(page 5). That is only 12%, so the other 88% represent a time when Her2 positive was the worst diagnosis.



The best thing about this study is not the data - (because treatments have progressed and much of this is not valid for our experience) - but the change in thinking about managing cancer long term. It changes from the wait and see and let progress to hey there are subtypes with definite recurrence patterns, lets manage care and surveillance with this in mind. It is a move to more personalized medicine.

And we cancer survivors say: Hey, lets use boosters to ward off recurrence. And why not?



In this study 22% progressed to MBC, another 5% to local regional and less than 1% to contralateral. Let us keep redefining who is progressing and take active steps to prevent recurrence beyond surveillance.

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[Ellie F]

Thanks for posting this information. I've waded through and hope I've grasped it! I think ER - PR- her2 + are classified as her 2 enriched?? Is this right? If so the second peak opens lots of thoughts for another year of a targeted treatment at 6 years! Wow that could be a game changer!

Ellie

['lizbeth]

Ellie,

Well . . . not exactly grasped, lol.

Yes, the Her2 positive, ER-, PR- is the Her2 enriched classification.

I think the idea of a booster of Herceptin is very sound. But an entire year of Herceptin at 6 years would likely be a little late and way too much treatment.

What is more practical is to have boosters that would precede the recurrence patterns in the subtypes. So if one is likely to recur at 24 months, the booster should be before to block that pathway and prevent the cancer from growing.

The concept of boosters of targeted therapies could be a game changer!!!! Yeah!

['lizbeth]

The problem is that we need the new patterns of recurrence with the addition of Herceptin in 2007 for adjuvant treatment.

In this study only 12% of the women had received Herceptin, so the current recurrence rates and patterns are a mystery.

['lizbeth]

Here is the type of information I was looking for. I'm sure this has been posted before, but likely in more advanced medical-speak. This gives us a picture of the positive changes brought about by the approval of Herceptin.

Ten Years Later, Trastuzumab Survival Advantages March On

Neil Osterweil
December 07, 2012

SAN ANTONIO, Texas — A decade of data continue to demonstrate that adding trastuzumab (Herceptin, Genentech) to standard chemotherapy in women with HER2-positive breast cancer improves both overall and disease-free survival.
Furthermore, the benefits conferred by trastuzumab are not waning over time.
At a median follow-up of 8.4 years, women randomly assigned to receive doxorubicin and cyclophosphamide (AC) followed by paclitaxel plus trastuzumab had a 37% lower relative risk for death than women who received AC alone, reported Edward H. Romond, MD, professor of medicine at the University of Kentucky Medical Center in Lexington.
For women with high-risk HER2-positive disease, the trastuzumab-containing regimen also reduced the risk of having a disease event by 40%.
These relative risk-reduction benefits were seen across nearly all subgroups, Dr. Romond said.
He presented data from the final planned joint analysis of overall survival from the NSABP B-31 and NCCTG N9831 trials here at the 35th Annual San Antonio Breast Cancer Symposium (SABCS).
"For patients with hormone-receptor-positive disease, the absolute reduction in the rate of distant recurrence as a first event continues to improve over time with the addition of trastuzumab, and reaches 9.6% at 10 years. For patients with hormone-receptor-negative disease, the absolute risk of distant recurrence as a first event is reduced by 9.6% at 7 years, after which distant recurrence from breast cancer is unlikely," Dr. Romond said.
A breast cancer specialist who was not involved in the study told Medscape Medical News that the long-term data are welcome but not surprising.

...there was a real plateauing out in terms of the risk of recurrence... Dr. Claudine Isascs

"There continues to be a growing benefit [of trastuzumab ] over time, and in the ER [estrogen-receptor]-negative subset of patients, it was nice to see that there was a real plateauing out in terms of the risk of recurrence after about 7 years, which is reassuring, as we're following some of these patients beyond that," said Claudine Isascs, MD, professor of medicine and codirector of the breast cancer program at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.
Dr. Romond presented data on 2018 women assigned to AC and paclitaxel, and to 2028 assigned to AC, paclitaxel, and trastuzumab. In each arm, about 45% of women were both ER-positive and PR-positive, and the remainder had tumors that were ER- or PR-positive, or both. About one half of all women in the studies had tumors ranging from 2.1 to 5.0 cm in size, and about 40% had tumors measuring 2 cm or less. Roughly 10% in each group had tumors larger than 5 cm.
In all, 102 women (5%) assigned to receive trastuzumab did not get the drugs because of cardiac symptoms or a decrease over baseline in left ventricular ejection fraction following AC. These patients were included in the intention-to-treat (ITT) analysis.
In the control arm, 413 women (20.4%) received trastuzumab after the first interim analysis of the trials in 2005 showed positive results; these patients are also included in the ITT analysis.
Ten-Year Data Similar to 6-Year Data
Six years after randomization, disease-free survival was 81.4% for patients assigned to trastuzumab vs 69.5% among those assigned to AC. Similar results were seen at 8 years (76.8% vs 64.9%, respectively) and at 10 years (73.7% vs 62.2%), for an absolute difference at 10 years of 11.5%.
Trastuzumab was associated with a hazard ratio [HR] of 0.60 (95% confidence interval [CI], 0.53 - 0.68, P < .0001).
Disease-free survival events included distant recurrences in 11.2% vs 19.4%, local regional recurrences in 4.1 vs 6.1%, contralateral breast disease in 2.3% vs 2.0%, and other second primary cancers in 3.3% vs 3.7%. In all, 1.9% of patients receiving trastuzumab died without recurrence, compared with 1.5% of patients receiving AC-paclitaxel only.
Among ER- and/or PR-positive patients, distant recurrence as a first event occurred in 12.7% of those who had taken trastuzumab, and in 22.3% of those who had not. Among ER- and PR-negative patients, the respective rates were 11.9% and 21.5%, and as noted above by Dr. Isaascs, the events in both groups began to level out at about 7 years but remained substantially better for trastuzumab-treated patients.
Dr. Romond noted that the absolute differences in overall survival between trastuzumab-treated patients and control patients has increased gradually over the last decade, from 2.9% at 4 years after randomization to 5.5% at 6 years, 7.8% at 8 years, and 8.8% at 10 years.
There were 286 deaths in the trastuzumab arm, and 418 in the standard chemotherapy arm. Deaths from the primary breast cancer occurred in 10.3% and 16.8%, respectively, and from a second primary cancer in 1.2% vs 2.0%.
Survival rates were comparable between ER- and/or PR-positive patients (HR, 0.61; 95% CI, 0.49 - 0.76) and ER- and PR-negative patients.(HR, 0.64; 95% CI, 0.52 - 0.79).
NSABP B-31 and NCCTG N9831 were supported by the National Cancer Institute. Dr. Romond has disclosed no relevant financial relationships. Dr. Isaacs reported that she is on the speaker's bureau of AstraZeneca.
35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-5. Presented December 7, 2012.



http://www.medscape.com/viewarticle/775835