Khrystne Haje, Metastatic Breast Cancer and a Convoluted Drug Development Story

                                                                        See People.com story here.

Actress Khrystne Haje was recently featured in a People.com article. The headline elicited much discussion among metastatic breast cancer patients. Written by Julie Mazziotta, the story can be found here: “Head of the Class’s Khrystne Haje Reveals She’s In Recovery from Stage IV Breast Cancer: ‘I Feel Fantastic.'”

Many Stage IV patients took exception to People.com describing the 48-year-old Haje as being “in recovery” and Haje saying “It’s all gone now! Now there’s nothing.”

Stage IV breast cancer is treatable but ultimately incurable. It is likely more correct to say Haje currently has no evidence of disease (NED) but there is no way of knowing the duration of her response. I certainly wish Haje the very best. She mentioned a drug I hadn’t heard of–I wanted to know more. But let’s start at the start.

Haje shared she was first diagnosed with invasive lobular breast cancer three years prior to her 2015 metastatic diagnosis. Invasive lobular breast cancer (ILC) accounts for 10 to 15% of all breast cancers. ILC is generally found in women in their 50s or older. It poses some imaging challenges–it can be hard to detect via mammography. (Actress Rita Wilson has early stage ILC.  Read more about LCIS here.)

For people with Stage IV disease, it’s important to know that ILC can have a different pattern of metastasis. In invasive ductal carncinoma, the common sites of metastatic disease are the lung, bones, liver and brain. However, in invasive lobular breast cancer, metastatic disease has been reported in those areas as well as GI tract, peritoneum, and retroperitoneum.

“I didn’t have cancer in my stomach,” Haje told Mazziotta. “But the radioactive PET scan showed that I had something by my liver, and something by my spleen, and something by my bowel. . . I had metastasized breast cancer.”

We don’t know what treatment Haje had prior to her metastatic diagnosis or her reasons for choosing a drug currently in the early stages of development.

What treatment did Haje have?  According to People.com, Haje has been given”the SM-88 treatment, which involved simply taking a pill and doing a subcutaneous injection once a day, every day. The treatment is non-toxic, with only minor side effects.” Mazziotta reports Haje “still takes the pills today, almost a year after she first started hearing that the growths were gone, and is hoping that the treatment will be approved by the FDA soon.”

There is nothing to suggest approval is imminent. To date, a Phase 1 trial has been conducted as well as some individual case studies. All told, it appears 25 people with breast cancer have received this drug. As with any drug in a Phase 1 trial,  much work remains to be done.   As many cancer patients know, it can take between 10 and 15 years to develop a drug, at a cost of about US$800 million. For every 5,000 compounds tested, it is estimated that only one will be approved for use in patients. A Phase 2 SM-88 clinical trial for breast cancer isn’t yet recruiting; a Phase 2 trial for prostate cancer patients is open.

Source: A Guide to Cancer Drug Development and Regulation

 

What is SM-88?  SM-88 apparently combines four drugs (three of which are FDA approved although not for breast cancer): phenytoin, methoxsalen, sirolimus as well as tyrosine isomers. Tyrosine isomers seem to be the secret sauce.  Here is Tyme CEO Steve Hoffman’s March 2017 patent filing on “Tyronsine derivatives and compositions comprising them.”

What is CEO Steve Hoffman’s background? According to biotech analyst David Bautz, Hoffman is an engineer who wanted to learn more about how electromagnetic radiation killed tumor cells.  Bautz further writes: “…tumor cells were viewed to be vulnerable due to the aberrant nature of their metabolism, and mechanisms defined in the literature were invoked both serially and in parallel to attack tumors using already developed agents. Also unusual was the conscious decision to eschew the use of any preclinical models to test the underlying assumptions in animals. Rather, based upon extensive reading and an effective understanding of the medical literature, a theoretical approach was developed to attack and kill tumor cells selectively while sparing normal cells; and this was then tested in people.”

What is the history of SM-88? In November 2011, Luminant Biosciences (the precursor company to Tyme) filed for approval of a clinical trial for SM-88 (then known as SMK) with the Institutional Review Board (IRB) of New York Downtown Hospital. The company enrolled 30 patients with advanced metastatic cancer in the single-center, open-label, proof-of-concept clinical trial between January and December 2012. As is generally the case for a Phase 1 trial, the patient population was comprised of patients who failed all available anti-cancer treatments and had the following cancer types: 14 had breast cancer, four had non-small cell lung cancer, three had pancreatic cancer, two had prostate cancer, and one patient had each of small cell lung cancer, hepatic cancer, tongue cancer, appendix cancer, thyroid cancer, colon cancer, and a cancer of unknown origin. Biotech analyst David Bautz reported that in an affidavit filed Feb 5, 2013 with the US Patent and Trademark Office, Jeanetta Stega, MD, PhD stated the following in regards to the 14 breast cancer patients who participated in the Phase 1 study:

Under an expanded access program, 57 individual case studies were also performed with the approval of New York-Presbyterian / Lower Manhattan Hospital IRB. Of these 57, 11 were breast cancer patients. Among the 11 breast cancer patients,  zero (0) had a complete response, four (4) had a partial response, three (3) had stable disease and four (4) had progressive disease. Source: December 29, 2016 Form 8-K.

All of the 30 patients in the Phase 1 trial had metastatic cancer and an expected survival of 3 to 6 months. All had either failed or refused all available treatment. Given these facts, I was surprised that 11 patients had only 1 prior systemic regimen. I would have anticipated more.

 

 

Who was the principal investigator on the Phase 1 study? Leonard Farber, MD, was the initial investigator. At the time, Dr. Farber was affiliated with New York Downtown Hospital (NYDH), a not-for-profit community hospital, serving lower Manhattan, affiliated with New York Presbyterian Hospital and Weill Cornell Medical Center. According to legal documents,  Dr. Farber applied for and received IRB approval for the study in November 2011. Prior to approval of the study, Farber asked Dr. Jeanetta  Stega for help in developing the protocol and patent application for the Luminant study. Dr. Stega, a research scientist  with NYDH participated as the principal investigator in numerous medical studies; was promoted to Vice President of Research; and became Chairperson of the Hospital’s Internal Review Board (IRB). (She recused herself from voting on Dr. Farber’s application.)

In 2012, Dr. Farber complained he was not receiving enough money from Luminant. He accused Stega of taking money from Luminant that he should have received, and resigned from the Luminant study. Dr. Stega then sought treatment for the study’ s patients from the NYDH and Luminant requested that NYDH take over the study.

 

What’s next for SM-88?

A Phase 1b/2 trial for prostate cancer is enrolling patients. A trial for pancreatic cancer is next. There are ongoing investigator initiated trials (IIT) at Mount Sinai, Mayo Clinic, Medical College of Wisconsin, University of  Rochester and Albert Einstein College of Medicine.

What did I learn? 

Things are seldom as simple as they may appear.  People.com is a great source of celebrity dish but not necessarily a credible source of cancer treatment news.  I gained new appreciation for Dr. George Sledge’s “Maxims for Cancer Researchers.”

“Quantity has a quality all its own,” asserts Dr. Sledge. “The scientific literature is mostly crud. This is true both in the lab and the clinic. Lack of reproducibility is endemic. One of the major reasons for this is the curse of small numbers: cell line experiments that use only one cell line (rather like treating a single patient and expecting to discover a universal truth), animal experiments with a few lonely mice, clinical trials with suspicious ‘descriptive’ statistics. Small numbers studies are particularly prone to overcalling results, and we, lemming-like, follow them over the cliff in our ever-recurring credulity.”

Last year, I heard a presentation where a new combination therapy was said to have an 89 percent response rate. Translated into English this meant that, in a preliminary, unaudited analysis, eight of nine patients had shown initial signs of response. The next time I heard the study presented (more patients, longer follow-up, external review of results) the response rate had dropped to 54 percent. Still respectable, but not the second coming of the Salk vaccine. Quantity has a quality all of its own.–Dr. George Sledge, Maxims for Cancer Researchers

 

 

The Biggest Challenges Facing Metastatic Breast Cancer Research

Kudos to Julia Belluz, Brad Plumer, and Brian Resnick for their wonderful July 2016 Vox article, “The 7 Biggest Problems Facing Scientists According to 270 Scientists.” As one of my nephews would say, “Nailed it!”

See http://www.vox.com/2016/7/14/12016710/science-challeges-research-funding-peer-review-process

The authors surveyed  270 scientists all over the world, including graduate students, senior professors, laboratory heads, and Fields Medalists. In a nutshell, they learned  that scientists’ success often isn’t measured by the quality of their questions or the rigor of their methods. It’s instead measured by how much grant money they win, the number of studies they publish, and how they spin their findings to appeal to the public.

Here are some of the seven points that really resonated with me, a woman living with Stage IV breast cancer who is relying on research to help me–or failing that–my family, friends and well, everyone. Please note that these points as I am relaying them are in reverse order of importance.

WHERE ARE THE CELEBRITY MOLECULAR BIOLOGISTS? Point No. 6  hit home for me: Science is Poorly Communicated to the Public. “If I could change one thing about science, I would change the way it is communicated to the public by scientists, by journalists, and by celebrities,” writes Clare Malone, a postdoctoral researcher in a cancer genetics lab at Brigham and Women’s Hospital.

Amen! The general public has no idea that breast cancer represents something that went wrong at the cellular level. It is not a punishment for eating too much sugar or too little kale. It is not God’s way of sending you a wake-up call. It means that something has gone wrong with some of your 30 trillion cells and they are growing out of control. The onset and progression of cancer is due to multiple dysregulated proteins and cellular pathways.

But according to musician and amateur molecular biologist Melissa Etheridge, “Cancer is just a symptom of our bodies being out of balance and the cure is to understand health. It’s to understand our bodies and our spirits—our souls—better. That’s the cure.”

 Melissa Etheridge was diagnosed with Stage 2 breast cancer in 2004. She had a lumpectomy, 15 lymph nodes removed and then  five rounds of chemotherapy and radiation. Apparently this is the basis of her expertise.

In her spare time, Etheridge dabbles in genetics, too.  In a 2015 she told AARP: “I have the BRCA2 gene but don’t encourage women to get tested. Genes can be turned on and off. I turned my gene on with my very poor diet.”

The article drew the ire of many, including a non-profit that advocates for those with hereditary breast and ovarian cancers. “Everyone is born with two copies of both the BRCA1 and BRCA2 genes, which play essential roles in preventing cancer,” wrote Sue Friedman, executive director and founder of FORCE. ” Individuals born with a change or mutation in one of these genes bear a higher lifetime risk of breast, ovarian, and other cancers than those without a mutation not because the gene is ‘turned on’ but because they lack a working copy of one of the genes involved in preventing cancer development.

Attention journalists–some celebrities are knowledgeable about their conditions–but please give some thought as to how these influential figures’ words and actions will be received. Angela Jolie, for example, seems well-informed about why her personal family history made a prophylactic mastectomy and oophorectomy a logical choice–for HER. However, please take the time to point out that MOST cancer is NOT hereditary–90 percent of ALL cancers  are considered sporadic, meaning they just happen. So in other words, the vast majority of us–in looks or genes–are not like Angela Jolie at all.

Another plea: Please remember those who won’t “kick cancer’s ass.” It’s not like we did something wrong or we didn’t try hard enough or we blew off doctors’ appointments. We are living with a chronic, progressive and ultimately fatal disease. Don’t treat us like losers or pretend we don’t exist. Think outside your pink ribbon expectations.  Breast cancer is second only to heart disease and lung cancer as the leading cause of death in women. Where are your lung cancer special sections? Pancreatic cancer is a devastating diagnosis–there is no early detection for this disease. Like ovarian cancer, it is a silent killer–where are those stories?

As someone living with the fatal form of breast cancer, I am so tired of self-appointed experts–celebrity and other wise–expounding upon a disease that they know little about. I am a member of United Airline’s MileagePlus program. I have been a passenger on many flights.  Amazingly, I have no insights on the science behind keeping a plane aloft, how to fly a plane or the latest pilot union grievances. Journalists: When interviewing a celebrity, please ask yourself, “What makes this person an expert? What is their understanding of basic human biology let alone the disease in question?”

MUST BE THE MONEY–the authors noted that US academic researchers need outside grants to pay for their salaries, assistants, and lab costs.  University funding is paltry–many faculty are expected to cover at least 75 percent of their salaries with grant money. Grants typically expire after three years–far too short a time to supply the kind of research needed for meaningful results in studying metastatic breast cancer. Research can take decades.

Our federal government is the largest source of cancer research funding and as Vox reports, “that pool of money has been plateauing for years, while young scientists enter the workforce at a faster rate than older scientists retire.” You can bash all the breast cancer non-profits all you want for funding more “awareness” than research. But where are the protests, the outrage over the federal government slashing research funding? The Moonshot is all well and good, but it can’t eradicate YEARS of federal penny-pinching and indifference when it comes to research. As Belluz, Plumer and Resnick observe:

Take the National Institutes of Health, a major funding source. Its budget rose at a fast clip through the 1990s, stalled in the 2000s, and then dipped with sequestration budget cuts in 2013. All the while, rising costs for conducting science meant that each NIH dollar purchased less and less. Last year, Congress approved the biggest NIH spending hike in a decade. But it won’t erase the shortfall.

The consequences are striking: In 2000, more than 30 percent of NIH grant applications got approved. Today, it’s closer to 17 percent. “It’s because of what’s happened in the last 12 years that young scientists in particular are feeling such a squeeze,” NIH Director Francis Collins said at the Milken Global Conference in May.

 James Watson was 25 years old when he co-discovered the double helix structure of DNA in 1953. Watson benefited greatly from the work and mentorship of older colleagues. Where are the James Watsons, Frances Cricks and Rosalind Franklins of 2016? Sadly, they are probably going into more lucrative fields–and they probably aren’t staying the US, either.

See http://actfornih.org/

There is actually a non-partisan group dedicated to  “seeking the immediate restoration of funding for NIH followed by steady, predictable budget support in the future to enhance lifesaving research for patients around the world.” Medical research in the United States is in crisis according to ACT for NIH. “Adjusted for inflation, NIH receives nearly 19 percent less funding than it did in 2003. Because of this decrease in funding, NIH must reject research proposals that could lead to future discoveries of cures and treatments for cancer, Alzheimer’s, heart disease, stroke, diabetes, and other diseases. Our brightest young scientists are turning to other careers, and  other countries now threaten our global leadership in biomedical research.”

Again, where is the groundswell of outrage?

PUBLISH OR PERISH–Researchers are under enormous pressure to publish–unfortunately, the need to amass credentials can sometimes lead to the publication for the sake of publication–we end up with white-bread-and-mayonaisse studies that will ultimately help no one–except the authors’ careers. Metastatic breast cancer research creeps along at a tortoise-like pace–meanwhile these MBC researchers are being lapped by hares, eager to advance their careers. Sometimes researchers–perhaps even unconsciously–may create studies that are heavy on hype but slim on actual meaningful results. Says Vox:

The consequences are staggering. An estimated $200 billion — or the equivalent of 85 percent of global spending on research — is routinely wasted on poorly designed and redundant studies, according to meta-researchers who have analyzed inefficiencies in research. We know that as much as 30 percent of the most influential original medical research papers later turn out to be wrong or exaggerated.

See www.mbcalliance.org

The Vox article does not specifically address metastatic breast cancer research funding. But the Metastatic Breast Cancer Alliance (MBCA) has identified the following roadblocks to MBC research:

 Funding

• MBC researc is  underfunded. MBC-focused research made up only 7% of the $15-billion invested in breast cancer research from 2000 to 2013 by the major governmental and nonprofit funders from North America and the United Kingdom. Specific scientific areas are understudied. The field of MBC research is relatively small. 
• Overall cancer research is also underfunded (0.1% of the Federal budget.) Other areas receive more funding including the military, farm subsidies and education.

Matched Tissue Samples

• To advance MBC research, better access to tissue is needed, including the primary tumor and interval blood samples collected and banked between the primary and development of the recurrent metastatic tumor.
• MBC tissue from different populations needs to be studied (e.g., MBC in younger, premenopausal women vs. MBC in older women).

Model Systems

• The previously available laboratory models for MBC research were discouraging but in 2013 and 2014, several laboratories have demonstrated interesting MBC models.
• MBC models need to be validated and standardized across laboratories.

Academic-Initiated Clinical Trials

• Academics have not focused enough on MBC (in basic research, clinical trials or cooperative groups), although focus is rapidly shifting to MBC as a priority
• MBC research is complicated, costly and time-consuming (e.g., early breast cancer studies in animals can be two or three months; MBC animal studies can take up to 9 months to run a single set of animal experiments).
• Lack of academic involvement has resulted in MBC trials being led by the pharmaceutical industry and business interests, including correlative science studies.

Epidemiology

• We need to better understand the epidemiology of MBC. How many patients have a recurrence? How many of these represent a metastatic recurrence? What are their treatments and responses? How long do they survive? We don’t know because our national cancer registry (SEER) does not track metastatic breast cancer recurrence–we only have incidence, initial treatment and mortality data. Very few people present with MBC as I did (10% or less). Unfortunately, this isn’t the  first breast cancer rodeo for most people with a Stage IV diagnosis. But we don’t have recurrence statistics. You cannot manage what you do not measure.

 

I was diagnosed with MBC in 2009. Over that time, US  cancer research funding dropped by about 20 percent. Come on! We’re counting on you, Congress! Give NIH the support it needs!

I am proud to be a board member for the Metastatic Breast Cancer Network (MBNC). We are a founding member of  the Metastatic Breast Cancer Alliance (MBCA). The Alliance is led by advocates and, since forming with 15 groups in October 2013, has grown to be the largest breast cancer alliance in the U.S. with more than 40 of the leading cancer charities, advocacy groups and individuals and pharmaceutical industry partners represented. The Alliance is working to address all of the above questions. This work is hardly glamorous–there are many meetings, conference calls, committee work and countless hours spent writing and reviewing documents and other tasks. Most members of the Alliance are busy with their regular job duties–as someone living with the disease, I am beyond grateful for their efforts. As you can tell from the Vox article, we have our work cut out for us.  It’s not easy, but we are making a difference and will continue to do so!

 

 

Actress Marcia Strassman Died From Metastatic Breast Cancer

Actress Marcia Strassman was one of very few public figures to openly discuss her Stage IV breast cancer

Marcia Strassman, the actress best known for her roles in “Welcome Back Kotter” and “Honey, I Shrunk the Kids” died from metastatic breast cancer  this month at age 66. My condolences to her friends and family.

Strassman was something of a hero to me because she was the only famous living person I knew with metastatic breast cancer. I have been on the same drugs as Strassman, so of course I took inspiration that she lived with the disease for seven years.

The actress was one of very few high profile people to talk about having metastatic breast cancer–see this Stand Up 2 Cancer video. Elizabeth Edwards was the last national figure in recent years to share her metastatic breast cancer diagnosis. When Marcia Wallace (the actress who voiced Mrs. Krabapple on “The Simpsons”) died last year, a close friend of hers said she died of breast cancer, but Wallace’s family initially denied this was the case. Understandably, Wallace’s family may not have known what happened.

Although Strassman freely acknowledged her Stage IV diagnosis, not a single news report used the phrases “Stage IV” or “metastatic” breast cancer. I hope I don’t sound petty–to her grieving friends and family I am sure this is is a small point and one that unfortunately does nothing to alleviate their loss.

But it is so important.

Two weeks ago, I participated in a meeting for Chicago-area people living with metastatic breast cancer. Attendees could put on different colored necklaces signifying their breast cancer subtypes: hormone-receptor positive, HER2 positive or triple negative. I was surprised that several women did not know this basic piece of information–one that is the road map to their care and treatment making decisions.

Had these people’s doctors told them the specifics of their disease? Had they asked? Do they understand their treatment plans? We will never make any progress against metastatic breast cancer if we pretend it is all one disease.

Saying that Marcia Strassman died of breast cancer after living with it for seven years somehow implies she died because she let her guard down and WHAM! breast cancer got her.

This is not what happened. When someone dies from breast cancer, they died because the cancer spread beyond the breast and eventually overwhelmed the body.

From published interviews, we know Marcia Strassman was a denovo metastatic breast cancer presentation. This means she was Stage IV from her first diagnosis–when her breast cancer was found, it had already spread to her bones–this is unusual, the majority of those diagnosed with metastatic breast cancer had early stage disease.

Strassman shared that she had lobular breast cancer–i.e., the cancer began in the milk-producing lobules. About 10% of all invasive breast cancers are invasive lobular carcinomas (ILC). (For reference, about 80% are invasive ductal carcinomas (IDC.) Lobular breast cancer grows in sheets–not lumps–and therefore doesn’t show up on mammograms well. (Strassman did in fact have regular mammograms, was a non-smoker and maintained a healthy lifestyle.)

With ILC, for any given stage or grade, the prognosis is similar to that of IDC. The pattern of metastases is slightly different vs. IDC–lobular carcinoma can metastasize to unusual sites, including the gastrointestinal tract, peritoneum, and adnexa (refers to uterus/ovary). Invasive lobular carcinoma is more likely to occur in both breasts compared with other types of breast cancer. ILC tends to occur later in life than IDC — the early 60s as opposed to the mid- to late 50s.

Strassman had a lumpectomy and then began standard of care for hormone-receptor positive breast cancer. According to a 2009 magazine article: “One drug, Femara, an aromatase inhibitor in pill form that Strassman takes every morning, starves tumors of the estrogen they need to grow. The other, Zometa, which is administered in monthly infusions in her doctor’s office, is a bone-building bisphosphonate that can slow deterioration in people with bone metastases.”

Strassman “endorsed” Zometa early on, but either she or the drug company chose to quietly drop the partnership. (The late Barbara Brenner, then the head of Breast Cancer Action, was critical of a 2010 SABCS luncheon featuring Strassman.)

People can do well with bone-only metastatic disease for a long time, often well surpassing the median survival time for Stage IV breast cancer which is two to three years. Although one source reported Strassman had been given 2.5 years to live upon her initial diagnosis, it’s unlikely any oncologist would have offered such a prognosis–they just don’t know. Strassman, with no visceral organ involvement at her diagnosis, would have been on the “good” end of a metastatic diagnosis.

Strassman did so well that, two years after diagnosis, a writer marveled at how good she looked: “Strassman doesn’t look like someone who’s battling a grave illness,” Linda Marsa observed.”Once her condition was stabilized by the combination drug therapy, she had surgery to remove remaining cancerous cells and several lymph nodes. Since then, bone scans have revealed no further deterioration, which is excellent news. She will take some form of therapy for the rest of her life. ‘This is cancer—but it’s a speed bump,’ Strassman insists. ‘You slow down, but once you pass it, you keep going.'”

Although bone mets can be painful and in some cases disabling, generally speaking, from what I understand, they are not immediately life threatening. When breast cancer spreads to a visceral organ–like lungs, liver or brain–that is a different kettle of fish. It should be stressed that some people can and do live with mets to these areas for a long time–but we are all different.

We don’t know exactly what course Strassman’s disease took–only that it almost certainly spread beyond her bones. But we do know one thing for certain: Marcia Strassman died from metastatic breast cancer.

Strassman and some friends talked about her Stage IV diagnosis in this 2009 interview.