New topic - unsolved mysteries of MBC

Longtermsurvivor

The following is something I wrote on the Ibrance 2015 topic that I hope stimulates conversation in the wider MBC forum.

It would be wonderful to hear from you too.

many thanks, Stephanie

xxx

Good morning Zarovka,

You wrote: "Also, I have a whole rant with supporting references about how women stable tumors and women who are NED don't have different survival outcomes, statistically. The point is that it may not matter much whether Ibrance keeps you stable or gets you to NED."

Would you be willing to post your well-researched and well-reasoned report (it's not a rant) in a new, separate topic here in forum 8?

Also, do you have references to what I used to know and have links for, but no longer remember?

The difference between PFS and OS (progression free survival and overall survival)?

My friend Musa Mayer explained this so well at bcmets.org, that I checked her references and came to believe it myself.

* Partial response or even NED do not = improved OS. This is, in part, because cost of treatment toxicities can offset benefits of disease response. But there is more to the story!

Other counterintuitive research findings are:

* The actually complicated truth of breast and prostate cancer screening not providing any OS benefit to large groups...only to a statistically insignificant # of individuals. They go on to swear that early detection saved their lives and everyone must get screened for a few to possibly benefit.

* BC advocacy groups' promotion of mammograms for all beginning at younger than ages recommended by experts who juggle data & numbers.

* The risks of over treatment for both early stage BC and MBC.

* The question of Waiting for symptoms before restarting chemo? in MBC.

And any other counterintuitive findings you care to comment on?

We do such good jobs of deconstructing:

* MBC is an instant death sentence (we know that outdated statistics are only part of the picture).

* The promotion of BC awareness in the USA rather than focus on the cure (thank you, Metavivor and MBCN).

* Ignorance about breast cancer in men and also LGBT folks - the transgender people are especially hard hit.

* Societal ignorance about the realities of living with MBC because of the partial information given by disease advocacy groups like Komen and others.

* Pinkwashing, pinktober, Pink Ribbons and the BC industry. See Barbara Ehrenreich's famous article, Welcome to Cancerland: A Mammogram Leads to a Cult of Pink Kitsch

Oh heck, there's a never ending list of research and reality ignored for profit, convenience, wishful thinking and ignorance.

Zarovka, please address what you like and I'll be interested to read what you or anyone else chooses to share about these and related topics.

warmest healing wishes, Stephanie

Longtermsurvivor

So, I did a little bit of footwork on the question of the relationship between surrogate end points like progression-free survival (PFS) and overall survival in human breast cancer trials.

The best article explaining how this works is:

Are progression-free and disease-free survival the new gold standard for cancer trials?

http://www.cancerworld.org/pdf/8995_pagina_39_43_eGranround.pdf

September-October 2015 I CancerWorld

Showing that a new drug can keep advanced cancers from progressing, or stop early cancers from returning, is quicker, cheaper and easier than showing that it helps patients live longer. But how can we judge in which instances these surrogates will accurately predict overall survival?

excerpt:

The clinical relevance of PFS is unclear. As an independent outcome, PFS/DFS is most clinically rele- vant when there is the smallest ben- efit in clinical trials in terms of gain as a potential surrogate (that is, when PFS/DFS is most strongly related to OS, and the time from PFS/DFS to OS is small). Conversely, PFS/DFS would be most beneficial in clinical trials as a surrogate when in fact it has least clinical utility.

The use of PFS/DFS as a primary outcome in clinical trials is likely to increase, but it should be used with caution and understanding of all of the issues that affects its validity as a surrogate marker for overall survival.

xxx

This article also points in an important direction:

Progression-Free Survival: Meaningful or Simply Measurable?

2012 by American Society of Clinical Oncology

Christopher M. Booth and Elizabeth A. Eisenhauer

http://jco.ascopubs.org/content/30/10/1030.full

…published literature on advanced breast…cancers have not supported the surrogacy of PFS for OS.

xxx

And this is a bit more language-dense, but will appeal to the real cancer geeks among us:

2010 by American Society of Clinical Oncology

http://jco.ascopubs.org/content/28/11/1958.abstract

Overall Survival and Post-Progression Survival in Advanced Breast Cancer: A Review of Recent Randomized Clinical Trials

2010 by American Society of Clinical Oncology

http://jco.ascopubs.org/content/28/11/1958.abstract

Everardo D. Saad, Artur Katz and Marc Buyse

Abstract

With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor-based assessments as the primary efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise.

We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials.

The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy.

The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines.

A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point.

PPS represents nearly two thirds of patient survival after on-trial disease progression.

Anonymous

The whole "Ned & stable don't mean anything" really frustrates me bc the only way to really know that it would mean the same thing no matter what would be to not treat people or purposefully not let it get to stable or Ned which they aren't going to do. Since every cancer is so unique to the individual even that might not be sufficient. There has been at least one study that has shown that Ned did make a difference & I'll post it below. The idea of not treating until symptoms bothers me as well bc I had 7-10 tumors with largest being 5.6 cm & I had not a single symptom.

I know you're wanting the studies though so here is the one I mentioned:

/www.cancernetwork.com/breast-cancer/mbc-patients-who-attain-no-evidence-disease-live-longer

Metastatic Breast Cancer Patients Who Attain No Evidence of Disease Live Longer

News | September 18, 2015 | HER2-Positive Breast Cancer, Breast Cancer

By Cancer Network Staff

The attainment of "no evidence of disease" (NED) after treatment for metastatic breast cancer (MBC) is significantly associated with prolonged survival, according to a new study. Patients who were HER2-positive in this group also survived longer than those who were estrogen receptor (ER) positive.

Previous studies have found that between 5% and 10% of MBC patients survive more than 5 years, and 2% to 5% live beyond 10 years. "This albeit uncommon but distinctive subset challenges the belief that MBC is universally fatal," wrote study authors led by Andrew J. Bishop, MD, of the University of Texas MD Anderson Cancer Center in Houston.

The new study aimed to characterize patients with MBC who attain NED status, to assess outcomes compared with those who do not. Results were published online ahead of print in Cancer.

Investigators reviewed results for 570 consecutive patients with MBC treated between January 2003 and December 2005. Ninety of these (16%) attained NED, which the researchers defined as a complete metabolic response on PET, or sclerotic healing of bone metastases on CT or MRI. The median follow-up period for those who attained NED status was 100 months.

For the full cohort of 570 patients, the 3-year survival rate was 44%, and the 5-year survival rate was 24%. In contrast, those survival rates in NED patients were 96% and 78%, respectively.

At 2 years, NED status was significantly associated with survival, with a hazard ratio (HR) for mortality of 0.23 (95% confidence interval [CI], 0.16–0.34; P < .001). This was similar at 3 years as well, with an HR of 0.20 (95% CI, 0.14–0.30; P < .001). The median survival for NED patients was 102 months from the time of attaining NED status, and the 5-year progression-free survival rate was 40%.

On multivariate analysis, patients who had HER2-positive disease had better overall survival than those with ER-positive disease, with an HR of 0.44 (95% CI, 0.21–0.90; P = .02). Trastuzumab use was significantly associated with progression-free survival.

After adjustments, several factors made it significantly less likely for a patient to achieve NED status: these included overweight and obesity, and triple-negative disease. Presenting with de novo MBC, having a single metastatic site vs multiple sites, and having undergone local treatment of the primary tumor were associated with an increased likelihood of NED status.

"Ultimately, this study provides findings to encourage further research into this subset of patients with MBC, and it provides a backbone of outcome data for clinicians to use when they are counseling patients who attain complete responses to treatment about potential outcomes," the authors concluded. They noted that the retrospective design does limit the study's interpretation.

- See more at: http://www.cancernetwork.com/breast-cancer/mbc-patients-who-attain-no-evidence-disease-live-longer#sthash.s8Ocu6om.dpuf

Original study found at — http://onlinelibrary.wiley.com/doi/10.1002/cncr.29681/full

Longtermsurvivor

Hi NBNotes,

Thanks for directing me to this interesting article on the importance of achieving NED in HER2+ patients with breast cancer.

I've requested a copy of the medical journal article it refers to. The article raised many more mysteries for me and I trust there are more solutions in the original article.

I'll report back when I learn more.

warmest of healing wishes, Stephanie

Longtermsurvivor

Another clue to another unsolved mystery:

How much follow up testing in MBC is extreme?

The very short version is In the study, "more than 12 serum tumor marker tests per year or more than four radiographic imaging tests per year."

I was very surprised, because I often read of more frequent tests in bco members - and that's correlated with aggressive treatment sand differences in end-of-life experiences.

Details follow in the Medscape article below.

Healing best for all, Stephanie

xxx

'Extreme' Testing Is Common in Metastatic Breast Cancer

Fran Lowry

May 12, 2016

http://www.medscape.com/viewarticle/863261

Despite unknown clinical benefit, excessive or "extreme" testing to monitor disease is common among elderly women with metastatic breast cancer (MBC), new research shows.

The testing that was analyzed in the study was of serum tumor markers and radiologic imaging.

In the study, more than one third of the 2400-plus women with metastatic disease were found to have had more than 12 serum tumor marker tests per year or more than four radiographic imaging tests per year.

These women were dubbed "extreme users" by the study authors.

The findings were published online May 9 in the Journal of Clinical Oncology.

"We wanted to study this issue because there are limited data on how to monitor patients in the metastatic setting," lead author Melissa K. Accordino, MD, Columbia University Medical Center, New York City, told Medscape Medical News.

"When you look at the guidelines, they are really very vague, and they don't offer a lot of details for how often people should be doing this," Dr Accordino said.

"When you look at the guidelines, they are really very vague."

When she and her group looked at what was going on at their own center, they found that they had high rates of tumor marker use, with a high proportion of patients undergoing tests for tumor markers each month.

"This led us to see what is going on elsewhere," she said.

The researchers used the SEER-Medicare database to identify women aged 65 years and older who were newly diagnosed with MBC between January 1, 2002, and December 31, 2011, and who had undergone disease monitoring.

Billing dates of serum tumor marker tests for carcinoembryonic antigen (CEA) and cancer antigen (CA) 15-3/cancer antigen 27.29 and CT and positron-emission tomography (PET) scanning were recorded.

They also looked at factors associated with extreme use and compared total healthcare costs and end-of-life healthcare utilization in extreme users with those of women who were not extreme users.

There were 2460 women with MBC identified from the SEER database who were eligible for analysis.

Most were white (85.4%), single (60.3%), and free of comorbidities (57.3%). Most (72.5%) had hormone receptor―positive MBC, and the majority (85.7%) were alive more than 12 months from the time of their MBC diagnosis during the study period.

Of these women, 924 (37.6%) were found to be extreme users of disease-monitoring tests.

Most of the extreme use was for imaging tests, which were conducted in 807 (32.8%) of the women. Fewer women (n = 222; 9.0%) were extreme users of serum tumor marker tests.

Extreme users were more likely to be younger than 80 years, to have ER/PR-negative cancer, to have had at least one PET scan, and to have had more oncology visits, Dr Accordino said.

The analysis also showed that use of serum tumor marker tests was linked with being of higher socioeconomic status, having at least one PET scan (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.42 - 2.88), and having a higher frequency of office visits (OR, 1.72; 95% CI, 1.10 - 2.68).

Women with ER/PR-negative MBC were less likely to be extreme users of serum tumor marker tests (OR, 0.59; 95% CI, 0.37 - 0.95).

Similar associations were found with regard to extreme use of radiographic imaging, with the exception of women with ER/PR-negative MBC (OR, 1.93; 95% CI, 1.50 - 2.49).

There was no difference in overall survival in women who were extreme users of disease monitoring in comparison with those who were not, Dr Accordino said.

"These are administrative data, so it's not the same as prospective data, but still, it was an important finding. Those women who were getting closer attention, perhaps by getting more scans and tumor marker tests, were not living longer, but they were not living shorter, so you cannot make the argument that they were sicker and therefore were getting more tests," she said.

Extreme users had higher costs of care following their MBC diagnosis, from the first year of their diagnosis to the last year of their life.

For extreme users in the first year after diagnosis, costs were 50.6% higher (95% CI, 40.7% - 61.1%). The mean cost of care was $56,249, compared with $37,121 for the rest of the study population (P < .001).

Extreme users also had more aggressive and costly end-of-life care.

In the last year of life, costs were 68.7% higher (95% CI, 54.2% 0 84.6%) for extreme users, and mean cost of care was $63,697 compared with $39,843 in the rest of the study population (P < .001).

These results highlight the need for prospective studies to answer important questions about what constitutes the right degree of disease monitoring, Dr Accordino said.

"We need to have some prospective studies evaluating different strategies of disease monitoring to see what the ideal frequency of monitoring is, and also how to monitor these patients," she said.

The findings may also generate some controversy, Dr Accordino added.

"Extreme use may be reflective of both patient and physician factors, and both of these may be targeted in the future to try and reduce spending. The big thing right now is the need for better evidence prospectively to figure out the risks and benefits of such testing and to help us form guidelines," she said.

Don't Blame the Patients

Gary H. Lyman, MD, MPH, codirector, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, and professor of medicine, public health, and pharmacy at the University of Washington, Seattle, pointed out that current guidelines from the American Society of Clinical Oncology (ASCO) and statements from ASCO for the Choosing Wisely Campaign discourage routine use of these tests for monitoring patients with MBC.

"There are no data demonstrating that their routine use improves patient outcomes, and especially advanced imaging is associated with considerable cost. Nevertheless, these tests continue to be used extensively in practice, and as demonstrated in this study, more than one third of such patients experienced extreme use of these tests, as the authors defined it," Dr Lyman told Medscape Medical News.

The factors associated with extreme use of tests are not surprising but are important to note, he added.

"It appears that extreme test use is associated with frequent clinic visits and accompanied by substantial higher overall costs. It is not surprising that the most difficult-to-treat group of patients with MBC, those with triple-negative disease, were more likely to experience extreme use as well as those with positive findings on a previous CT scan, which may be used to assess disease progression or response," Dr Lyman said.

He does take issue with the authors on one point, however.

The term 'extreme users' seems to impart a responsibility entirely on the shoulders of the patients.

"The only issue I might take with the authors' report is that the term 'extreme users' seems to impart a responsibility entirely on the shoulders of the patients. I would guess this is semantics and not the intended message of the authors," he said.

But Dr Lyamn stressed that responsibility for testing ultimately lies with the provider and professional organizations. More education is needed to ensure that all parties know that there is a lack of supporting evidence for such practice and that clinical guideline recommendations do not support these practices, he said.

Dr Accordino and Dr Lyman report no relevant financial relationships.

J Clin Oncol. Published online May 9, 2016.

Free full text at http://hwmaint.jco.ascopubs.org/cgi/content/full/JCO.2016.66.6313v1

Heidihill

Can't seem to make these figures smaller but just as well for those reading-challenged like me. They are from the original article in nbnotes' link (thanks, nbnotes!), which is not just about HER2+ metsers. I'm surprised that Stage IV de novo (top curve in figure C) has better survival statistics at 5 years from time of distant mets than those who presented at stages IIIA, B and C. I wonder what the curves from date of presentation would look like. 

Longtermsurvivor

Hi everyone,

I have a copy of the article and am happy to share it, if you PM me with your email address.

Hope to sit down and pore over it soon, but am currently busy with a few surprise tasks. Plus terminal cancer.

Love and peace and happiness,

Stephanie your California hippie friend

xxx

Listen to a true loving kindness song! Select # 4 on Soul House. It's like a juke box of Tim Weed's en-couraging music. Great for sing alongs!

http://www.timweed.com/music.html