DCIS & Neoadjuvant treatment - moving discussion to a new thread

['lizbeth]

This information is provided by AussieGirl. Since more and more studies and patient treatments will involve neoadjuvant treatment - it is a good topic for us to explore.

Here's one article http://www.ncbi.nlm.nih.gov/pubmed/21667238

and here's a recent book chapter of interest which suggests that Herceptin added to neo-adjuvant chemo helps get rid of HER2 DCIS providing more complete responses. http://books.google.com.au/books?id=...0chemo&f=false

In the pathology literature, it is well known that DCIS is the last thing to go when we have to assess specimens for complete pathological response. The DCIS cells often looks "sick", like they are ill and dying, but we don't call it complete response unless the bad cells have disappeared.

So the neo-adjuvant therapy has an impact on DCIS but if it is incomplete, what does it mean?

I found this study http://jco.ascopubs.org/content/25/19/2650.full
which suggests the residual DCIS doesn't affect disease free survival.

Then this one showing that residual DCIS post-neoadjuvant Rx is bad. (my translations in red)
http://jco.ascopubs.org/content/30/15/1796.full
"We conclude that pCR defined as ypT0 ypN0 (=no residual tumor) is associated with highly favorable outcome. ypTis (=residual DCIS), ypT1mic (=residual microinvasion), and ypN+ (=residual positive node)residuals only are associated with increased relapse risk and should therefore no longer be considered as pCR. Extent of residual disease and evidence of regression provide helpful additional prognostic information. pCR is a suitable surrogate end point for patients with HER2-positive (nonluminal), TN, and luminal B/HER2-negative tumors but not for luminal B/HER2-positive and luminal A tumors. "

Also earlier in this article:
"We further demonstrate that in subgroups considered to have slowly proliferating tumors, pCR is not associated with prognosis, whereas in subgroups with highly proliferating tumors, pCR can discriminate between patients with good and poor prognosis accurately. The recently proposed clinicopathologic definition of the St Gallen panel nicely recognizes these subgroups. In fact, prognostic impact of pCR is highest in HER2-positive (nonluminal) and TN tumors, where patients achieving pCR show a prognosis comparable to that of patients with luminal A tumors.
Surprisingly, pCR was not prognostic in the luminal B/HER2-positive subgroup irrespective of trastuzumab treatment. In this subgroup, pCR rates were low, despite concomitant anti-HER2 therapies,11,28,29 but similar outcomes were observed in the adjuvant trastuzumab studies.30"

SO...
I think treatment of DCIS with neo-adjuvant chemo is a work in progress - the residual DCIS gets cut out anyway, or at least zapped with radiation, so it wouldn't be a big surprise if eventually residual DCIS is shown not to be so important if a mastectomy is performed.

However, it'd be good to know if you could have neo-adjuvant chemo followed by Limited surgery (or perhaps No surgery, on the basis of core biopsies as an assessment of response. )

And how will neoadjuvant Perjeta work on DCIS?? So much to learn!

['lizbeth]

AussieGirl,

It has been very quiet eh? I've been chewing on this.

Recently there was all the press about not treating DCIS as a "cancer" and many women are not pursuing surgery for treatment. I find this interesting and contradictory to the neoadjuvant pCR with DCIS and the associated prognosis.

I did note from Neosphere, that the neoadjuvant pCR rate was about 40%, and from Tryphaena - adding anthracyclines increases it to the mid to upper 50s. Skipping the anthracyclines,and offering Taxotere, Perjeta Herceptin with Carboplatin increased pCR to 63.6%.

StephN brought up the TOPOII connection to anthracyclines. I would be interested in seeing a study that compared an arm of genetic profiling to functional profiling before neoadjuvant treatment. It is time for randomized studies to go the way of the dinosaur. I think functional profiling for CLL was a prudent FDA approval. And it time to start separating who benefits from neoadjuvant from the patients who are better served by surgery first.

So from my observation - Perjeta is effective, but adding the platinum salt increased pCR by 24%.

The question is: How does DCIS look under the microscope with Carboplatin?

Also, when will Perjeta be approved for early breast cancer in Australia? Do you follow NCCN guidelines or is there a set of Australian guidelines?

Thanks!

[Aussie Girl]

hey ' lizbeth,
I'm day 3 of 6th chemo cycle. Have no brain function just now!

Not sure who on this forum has best insight into therapies. I've mainly been learning about adjuvant for my own decisions and neo-adjuvant has so much new stuff. In a while I'll check out our Australian EVIQ site which has links to recommended protocols. Australian govt pretty tight with money for new drugs at the moment....new government has the knife out for most essential services unfortunately.

Aussie Girl

[Coux92]

Aussie Girl, 6th cycle.... Means your done right? Congratulations!!!!

[roz123]

hmmmm interesting
I had pcR or complete response and 1cm of residual dcis - my docs told me that is a complete response because there were no active invasive cancer cells left after chemo as tested by pathology. They said because dcis does not behave like idc chemo would not have much of an effect on it.

am I luminal a or b being triple positive????

['lizbeth]

Oh poor AussieGirl, round 6 - the brain function is toast! But good observation Coux92,time to celebrate!

Roz123, I've been up most of the night right up Black Friday sales, my brain function is also nil . . . but isn't Luminal A the best one? Let's pick that one!

[sarah]

HER2+ and DCIS is a dangerous combo and should be treated aggressively. I started with DCIS. I went to a top female oncologist at City of Hope (now well respected!!!) who said I didn't need Herceptin!!! and mastectomy was the only needed treatment and that she felt was "aggressive" treatment!. 4+ years later, I had invasive cancer and was in serious trouble so yes, DCIS should be considered cancer and should be treated aggressively. Don't risk your life. I kept asking about Herceptin and was constantly shot down, that was in 1999, thank goodness today Herceptin is given always. In my mind not calling DCIS cancer is stupid and dangerous. We may need sub names for the different cancers to help better define treatment but if it can become a fully aggressive cancer as mine did, it is cancer. Let's be serious and careful. I do not want any HER2 people to have to go through what I've gone through when a solution would have been so easy. I am lucky to still be here given that my doctors back then were so unknowledgeable and unwilling to go that extra mile for me. I knew back then that I needed Herceptin to be safe but everyone told me that I didn't and refused to give it to me.
Sarah

['lizbeth]

@Sarah,

I believe patients & doctors have been conditioned to think of DCIS as an indolent form of pre-cancer. This characterization could be the case for many patients.

However, this thinking lacks the personalization of analyzing each individual's cancer and is based on assumption instead of reality.

Back in 1999 - it would not have been acceptable practice to give a patient with DCIS the drug Herceptin. We can all look back and realize how prudent it would have been for you to receive trastuzumab. The thinking when the drug was being tested was that the higher the expression of Her2 receptors the more effective the drug would be. The focus was on those with Metastatic Breast Cancer - whose disease was so evident and situation was so dire. Your doctor would not have been able to act beyond Standard of Care without a clinical trial. Trials for DCIS and Herceptin in 1999? I suspect that did not exist.

Many young doctors can be very arrogant. Keep in mind that the deaths caused by the medical field is staggering:

According to the most recent research1 into the cost of medical mistakes in terms of lives lost, 210,000 Americans are killed by preventable hospital errors each year.
When deaths related to diagnostic errors, errors of omission, and failure to follow guidelines are included, the number skyrockets to an estimated 440,000 preventable hospital deaths each year!

You have the experience with DCIS and can sound the alarm to take it more seriously - an unfortunate expert, but others can benefit from you experience. Luckily for us - you are still here to share your story.

We need to be each other's advocates.

It is important to identify subtypes of cancer, and DCIS. Currently there is a large group of cancer patients which are being overtreated by chemotherapy (over 50%) and a small group that is being undertreated (small tumors & DCIS).

[Aussie Girl]

Hello Ladies,

I'm sorry to hear about your experience, Sarah. I can understand your passion!

I haven't got the resources I would have at my work at the moment so I'm using the net and my memory here.

DCIS is present in two situations - pure DCIS and DCIS associated with invasive carcinoma. The latter is treated primarily according to the invasive component. I'm going to focus on "pure DCIS" for this post.

Sometimes a diagnosis of pure DCIS is made, but there is hidden or occult invasive carcinoma present. This can be straight misdiagnosis or a sampling problem by pathology. Note that you cannot process every bit of a lumpectomy (unless it's small) or mastectomy for pathology - representative samples are chosen to be examined. There is not enough money and there are not enough pathologists in the world for every bit to be sampled. Our laboratory in Austraia makes no money out of Breast surgical specimens, these complex tests are cross-subsidised by the small skin and gut biopsies we do.

If high grade DCIS is found, a sentinel node biopsy is often done in many centers, particularly if the DCIS is over a large area because of the risk of occult invasion and the possibility of a node met.

Even if there is diagnosis of pure DCIS is correct, invasive carcinoma can develop in remnant breast tissue or on the other side. This is because all the breast tissue has been subject to carcinogenic forces over the patient's life.

The 10 year survival of pure DCIS is 96-98% (98% in recent years) but the risk of recurrence of either further DCIS or invasive DCIS after an initial diagnosis of pure DCIS found on an excision specimen is quite high over time, varying from 1 to 3-4% per year. The higher figure is for high grade DCIS. A woman with DCIS is 3.9 x more likely to get invasive breast cancer than the average woman. One meta-analysis showed women <40 years at the time of diagnosis have an 89% increase in risk of ipsilateral breast tumor recurrence (IBTR) compared to women >40 years at diagnosis. http://jncimono.oxfordjournals.org/content/2010/41/121

SO: pure DCIS needs to be excised if possible, especially if high grade, +/- sentinel node, radiation and/or tamoxifen. The benefit of systemic chemo hasn't been proven (the maximal possible benefit would be 2% at most because the survival is already good). There is no real place for neo-adjuvant therapy in pure DCIS as you can't diagnoses pure DCIS without excision anyway.

Below I include some links to suggest that a little anti HER2 therapy, given at the time of therapy may help reduce later recurrence of HER2 positive DCIS but the evidence is still not in.

Low grade DCIS is a different disease to high grade but usually has the same treatment, but I might write more about this another time.

CLOSE FOLLOW UP OF DCIS IS CLEARLY WARRANTED!

DCIS is also divided into grades (low, intermediate and high grade) and into subtypes on the basis of appearance and receptor/ HER2 status. About 50% of high grade DCIS is HER2 positive. HER2 positive DCIS is often seen in association with HER2 negative Invasive duct carcinoma as well as with HER2 positive invasive carcinoma. When HER2 status is reported, it is very important that it is the invasive component that is assessed.


Some interesting links:

2009 Seminar for patients about DCIS. Very discursive but covers many of the issues in an intelligent way
www.lbbc.org/content/download/1311/9974/file/LBBCdcis09.pdf

General info about DCIS on cancer network. You may have to get a member login
http://www.cancernetwork.com/cancer-...-breast-cancer‎

MDA Anderson Centre: Dr Kuerer discusses DCIS, including an indication that one dose of IV Herceptin in treatment of DCIS may be beneficial.
http://www2.mdanderson.org/depts/onc...0-compass.html

DCIS and Lapatinib - ongoing trial
http://www.clinicaltrials.gov/ct2/sh...ductal&rank=1]

That's all for now

Aussie Girl

[Aussie Girl]

Roz

Luminal A and B refer to oncotype DX type analysis and are ER+ subtypes. Luminal B is higher grade than luminal A and may require adjuvant chemo + anti-ER therapy. Don't worry about it. This primarily a research tool and if your are HER2 positive you are in the HER2 encriched group. "Luminal B/ HER2+ category is ER+ HER2+ high grade invasive carcinoma. Use of this particular category (as opposed to just HER2+ cancer) is always accepted as a category.

Aussie Girl

[sarah]

well Aussie Girl, sounds like you've done your research. Good luck and good health
sarah

[linn65]

As you know I had pre-adjunctive therapy, and my tumor's stayed the same which the doctor considered that a good response. However, my final path changed from the first 1. Grade two and moved to Grade 3 that isn't better. Also, angiolymphatic and extracapsular exposure, and I will never know if that progressed while on treatment or not....Could I of??

Lizbeth, can you just break it down in terms I can read.

['lizbeth]

@Linn65 - I will look into it with AussieGirl's help, but my sister is coming over for a massage right now. I just typed this up and was copying it over when I saw your post.

@Sarah - what was your age at diagnosis with DCIS? I am curious about the follow up you received and how was the subsequent cancer discovered? Was your cancer hormone receptor positive or negative?

@Roz - AussieGirl points out the gap between research medicine and mainstream medicine. Most of us do not have access to the pathology of our cancers in such detail. I did notice the Spanish study examined Her2 subdivided into Her2 enriched and a new designation Luminal-Her2.

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.

http://her2support.org/vbulletin/showthread.php?t=59367

So, as cancer patients, we run into a wall of “Standards of Care” in the medical field – as compared to what we wish for, more subdivision and personalization of treatment. I’m not blaming physicians for this – as the hospital administration, liability lawyers, insurance companies, pharmaceutical companies, and a multitude of reasons have brought us to a medical system that turns like the Titanic. The iceberg of cancer looms ahead, difficult at times to detect, with the largest danger still hidden under the surface of what we can see.

The point: even if you were to know more about the pathology of your own cancer – it wouldn’t affect your treatment options with mainstream medicine. We could look for a clinical trial, but most are focused on initial treatment, and recurrence treatments. Slamon is working on ER positive treatments, but I don’t know how far he has drilled down into subtypes. I think most research remains in the theory stage on subtypes and recurrence patterns. Knowledge is power, and you can use what you learn to seek alternative treatments, diet & exercise changes, etc to work for a better health outcome.

@AussieGirl, thanks for letting us challenge you during a suboptimal time (chemo) and for taking the time to share the research and your experience with us. I pick on your chosen profession (physician) quite a bit, but I love the fact that you are a Pathologist. I think many of us on the board would love a field trip to visit you, your microscope and some very interesting cells! I am skeptical of some numbers – such as the pure DCIS recurrence rates. I think the industry does a good job of tracking initial diagnosis and deaths – but the recurrence rates do not make sense to me.

Another thing I experienced, and perhaps Sarah too – the follow up at an earlier age with symptoms of cancer or pre-cancer was inadequate. I wish I had known the importance at age 37 of follow up. My nurse made me feel like such an idiot for being concerned about nipple inflammation. Six years later I had 2 Pagets lesions that was only detectable by MRI, and thankfully an IDC lesion detectable by Mammogram.

Back to the DCIS discussion . . . I was focusing more on the importance of DCIS with a diagnosis of IDC. Standard thinking might be faulty on the DCIS component – the IDC cells are dead, the DCIS still lives (barely). Is surgery & treatment affecting DCIS in a negative way to affect the cells to adopt a more aggressive function?

Neoadjuvant treatment is changing the way we already look at cancer. It is exciting to see the information that is coming from more emphasis on pre-surgery treatments.

['lizbeth]

@Linn65,

A quick look - I can't describe your neoadjuvant as progression. I do see the cancer adapting to the changes in the environment caused by neoadjuvant treatment. I do not see the information available about the nodes prior to treatment. Did you have PET done prior to chemo?

Lani had talked about this in a prior post about the vaccines - Her2 changing to Triple Negative. In your case the cells became more expressed in ER.

Perhaps we should explore a bit more about ER positive cancers in a new thread. I'll start one a little later.

Hugs my friend.

[linn65]

Are you getting the message???? If so LUCKY GIRL!! Sounds nice.

[linn65]

I had it in 1 node based on physical exam (I had felt it too). They biopsied the node to so they could say it was cancer. Before my first chemo I had a catscan, breast mri, bone scan. Then chemo, then masectomy, followed by radiation......and as you know no scans unless I have symptoms, and I will know if that happens because it sounds like it will be pretty painful if thats the case most of the time.

My K167 went from 80 to 55%, my ER went from 30% to 73%

[sarah]

Hi 'lizabeth, it was 1999 when herceptin was only given to metatastic patients and only beginning. I was 52. no nodes. ER/PR positive. surgery that was it, can you believe it! and went to a "top" oncologist (woman) at City of Hope, should call her hopeless!!! She explained what all the markers meant and which were dangerous but felt a mastectomy was enough despite my continuous questions about herceptin. Lucky to still be here. recurrence just under 5 year mark. France threw everything at me, saved me from sudden death and no insurance hassles and people come around and give you manicures or pedicures, massages and stuff while you're doing chemo!!! and they don't want you to suffer pain or have anxiety and generally the rooms have lovely views of the sea! and you can have wine with your lunch! I didn't, didn't think it would mix well with chemo.
These days they say you should stay on anti-hormonals for 10 years not 5. I did 6 but that was in the days, 5 was the protocol and I did 6 years of herceptin after the chemo and radiation (had herceptin during the chemo and radiation also).
I wonder if it pays to go back onto an anti-hormonal since the protocol has changed to 10?
wish all of you luck with your treatments and health
I guess my view is do more than less and fight for it
Health and happiness
sarah

['lizbeth]

Darn - I wish I could have had my infusions in France. I would have loved to have a pedicure and some wine from Alsace, a nice Reisling with lunch.

I had tubs of ice, an easy chair and lots of blankets.

@Sarah - I hear the anger with the oncologist. I think it is time to let that go. She was following what was known at the time. Herceptin wasn't approved for Metastatic Breast cancer until several years after your diagnosis, Primary Breast cancer in 2007. Herceptin for DCIS , unheard of in 1999. You knew you needed it - but this oncologist, or any other oncologist wasn't in the position to offer it to you. Not even off label.

Today with a DCIS diagnosis you might be able to get access. She wasn't a bad doctor with the initial diagnosis & treatment- you were ahead of mainstream medicine.

The follow up might have been less than ideal. How did you find the recurrence?

['lizbeth]

I posted a current study on DCIS, radiation and Herceptin under clinical trials. This study ends March 2019. It has an arm with Herceptin infusions in Week 1 and Week 4, combined with whole breast irradiation. The comparative arm only has radiation.

Sarah - this will be one to watch with interest. Could it be that the Herceptin you wanted in 1999 takes 20 years to be approved for DCIS?

['lizbeth]

I also posted AussieGirl's study on Tykerb and DCIS in an earlier post on this thread in the clinical trial section. The Phase I/II study completes next year.