Neoadjuvant Chemo spreads Cancer?

Lisey

So someone posted this is in another forum and I initially thought it was 'alternative'.. but it looks like it's from Science - a leading journal. Has anyone else read this? What do you make of it?

http://stm.sciencemag.org/content/9/397/eaan0026

Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.

Lula73

I'm not saying the article and research is not valid, however this is not a major medical journal on par with JAMA or New England Journal. Its impact factor is just under 17 while JAMA is 44 and NEJM is 72 (higher numbers are better). Even the abstract does not follow proper form for a legit clinical paper. Additionally this study was done using tissue in a lab using a murine model and tissue transplanted into another species (xenografts). Do you know how many "cures" and treatments for diseases have worked beautifully in a lab but when it's time for human trials we find out it doesn't quite work the same and it gets scrapped? Again not saying it isn't valid but only a journal with an impact factor in the low range would publish it...

KayaRose

Every time you think it's safe again to go in the water....... This article absolutely terrifies me. The thought that all that pain and suffering I went through during chemo treatments may actually have spread the disease rather than destroy it - well, it's almost too much to handle. Seriously.

MinusTwo

KayaRose - calm back down. There are TONS of serious research articles that show neo-adjuvant chemo shrinks tumors - or they disappear entirely. Not to mention the women on this thread who have had great success.

I don't pretend to understand the article, but I agree with Lulu. I hope someone like Barred Owl or Beesie will weigh in because I find it very difficult to believe that it's not either an anomoly or relates to a very small percentage of rare tumors.

BarredOwl

The article was not published in "Science" magazine. It was published in a different, much newer journal from the same publisher, named "Science Translational Medicine":

http://www.sciencemag.org/site/marketing/stm/definition.xhtml

"Translational medicine" seeks to bridge the gap from the laboratory bench to bedside. As noted at the link above regarding the establishment of this journal," translational medicine builds on basic research advances - studies of biological processes using cell cultures, for example, or animal models - and uses them to develop new therapies or medical procedures."

There are already two threads on this research paper, including this one in this same Forum:

https://community.breastcancer.org/forum/73/topics/856687?page=1#post_5000730

I question the need for initiating yet another thread.

BarredOwl

MinusTwo

Thanks Barred Owl. We were posting at the same time. I think the subject line is inflammatory.

KayaRose

Thank you both. I'll read your references and check out the other thread. Still, once that feeling of dread invades me, it's hard to shake. Unfortunately, I simply don't understand some of what's presented in these studies as well as you ladies do and I very much appreciate your explanations.

Lisey

thanks for posting the thread Barred. I did search and didn't find it.. their title is a little vague. It appears this study is being used to try to stop the mechanism for spread, which is a good thing.

exbrnxgrl

Thanks to all who made some important points regarding the article. While it is worth noting the findings, it is far from being conclusive and should be taken with a hefty grain of salt at this time. There is no need for patients considering neo-adjuvant therapy to panic.

BarredOwl

I agree that this study has significant limitations and does not negate the existing body of clinical research demonstrating improved outcomes with neoadjuvant chemotherapy.

Critically, one press feature noted that lead author Dr George Karagiannis says the findings, published on Wednesday, should NOT deter patients from seeking treatment.

The import, caveats, and limitations of such a study are not clear from an abstract, press report, or summary. Should one access the full-length paper and data supplements, one must understand that a single pre-clinical research publication is NOT a suitable basis upon which to make treatment decisions. Scientific research findings must be interpreted appropriately and within the context of available clinical evidence therapeutic efficacy.

For those with pending treatment decisions, all outside information, particularly such early stage work, should be discussed with your medical oncologist, because of the danger of over-interpreting and/or misapplying the results of basic research that have no current clinical application.

Additional Remarks:

I already commented in the two other threads (see e.g., https://community.breastcancer.org/forum/73/topics/856687?page=1#post_5000730). Here are some additional comments.

This study used mouse models of neoadjuvant chemotherapy in which animals did not receive surgical treatment prior to drug treatment. In my opinion, it is not appropriate to extrapolate these findings to the adjuvant setting.

The limitations of mouse models have been noted above. Most of the mouse experiments used paclitaxel regimens and some used doxorubicin/cyclophosphamide (in either case without surgical excision). There appear to be potentially conflicting studies with respect to some findings. For example, the authors state: "Our findings in the PyMT model are in discrepancy with the Coussens group (44)."

Two aspects of the work assessed clinical samples from limited numbers of patients with ER+ HER2- disease (described as "locally advanced invasive ductal carcinoma"), who received a specific neoadjuvant chemotherapy ("NAC") regimen, and who all had residual disease (residual cancer burden (RCB) score 2 to 3):

(1) TMEM Density (20 samples)

"The change in TMEM density in post-NAC specimens was evaluated in 20 patients with ER+/HER2− disease, who were treated with weekly paclitaxel for up to 12 weeks followed by four cycles of doxorubicin plus cyclophosphamide and had residual disease after NAC [residual cancer burden (RCB) score 2 to 3]. None of the patients received pre-operative tamoxifen."

Additional details indicate that the 20 ER+ HER2- patients received a neoadjuvant regimen including "weekly paclitaxel (80 mg/m2 × 12 consecutive weeks) followed sequentially by dose-dense AC chemotherapy [doxoru- bicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks × four cycles, plus pegfilgrastim (6 mg, subcutaneously) on day 2 of each cycle."

(2) MENA[INV] expression (7 samples or 5 samples)

"[W]e compared MENA[INV] expression in pre- and post-NAC samples. We observed a significant increase (P < 0.01) in MENA[INV]-positive area between pre-NAC biopsies and post-NAC tumors (Fig. 7, D and E)." They were only able to perform this on seven (7) of the patients.

"In addition, we analyzed MENA[INV] expression by qRT-PCR in fine needle aspiration (FNA) biopsies taken before and 1 week after the second dose of weekly paclitaxel in an independent small cohort of patients (n = 5)." In this case, the sample size was five (5) patients.

Independent researchers may or may not be able to replicate some or all of the findings.

They studied patients who all had residual disease after neoadjuvant therapy, and all of whom were ER+ HER2-. None were triple-negative. None were HER2-positive. Yet these are the subsets known to have the most robust responses to neoadjuvant chemotherapy or chemotherapy plus HER2-targeted therapy.

Apart from such specifics, the study has additional limitations, for example:

"One limitation of this study is that it does not fully address the development of clinically detectable metastases, which involves other processes such as release from dormancy and tumor growth in addition to cancer cell dissemination."

Perhaps the most important limitation is one related to clinical relevance [emphasis added]:

"Another limitation is that, due to a long time between the diagnosis and the relapse in ER+ disease, this study could NOT provide evidence that increased TMEM and MENA[INV] in post-NAC patient samples correlate with metastatic outcome." Thus, further research is needed to confirm and extend the findings: "A follow-up study is needed to determine whether patients with an increase in TMEM score upon NAC [neoadjuvant chemotherapy] develop distant recurrence more often than those without an increase in TMEM score."

BarredOwl

JaneSheridan

Hi Ladies - thank you Barred Owl. I just stumbled on this and am totally freaked...

Traveltext

Yes, this article is doing the rounds of many different social media forums and freaking out those of us who underwent neoadjuvant treatment. I've read it, skimmed it really, so thanks BarredOwl for bringing your scrutiny of the study to the table here. Not having achieved complete pathological response post mx, I'm very aware that recurrance is an option for me. But my surgeon wouldn't operate on my wildly inflamed breast, so I'd likely not be writing this if my treatment didn't start with chemo. And I know that if aggressive cancers come back, it's generally early on, so as each year rolls by I feel less worried.

Shellsatthebeach

The optimal sequencing of local and systemic therapies in the multimodality care of patients with breast cancer has been examined by several groups. Multidisciplinary trials, such as the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial and European Organisation for Research and Treatment of Cancer Trial (EORTC) Trial 10902, established that patients who undergo NCT for breast cancer have disease-free and overall survival rates similar to those of patients who undergo surgery first followed by adjuvant systemic therapy.4–7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347926/

new_direction

we need better treatment options. I needed chemo to shrink the tumor but I feel survival lies in my own hands to "experiment" with possible strategies

Chillintime97

i am waiting for biopsy results they are discussing neoadjuvant with me I really freaked out when I saw this paper. wouldn t it be best to just take the boob and the lymph nodes then do follow up? The idea that it increases vascularity of tumor scares me to death.

Lisey

I think chemo helps the majority of breast cancers. HOWEVER we must recognize that there may very well be a subset of tumors that actually get more aggressive with chemo. Research cancer stem cells - which typically are not killed by chemo and decide for yourself.