Tag Archives: lobular breast cancer

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



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What have we learned about Metastatic Breast Cancer, Charlie Brown?

Did-You-Know-Logo-SmallI am coming up on my fifth year of living with metastatic breast cancer. I am fortunate–I started with a low volume of bone mets and five years later my disease has remained fairly indolent. Not everyone is so lucky–and believe me, it is only luck. It isn’t like I tried harder or did anything special–I was just “lucky” enough to have a “kind” of breast cancer (ER/PR+; HER2-) and bone-only disease that has been fairly low key. I try not to take this for granted.

As I think back to what I knew about breast cancer in 2009, I am embarrassed. I really didn’t know anything. I remember puzzling out the facts of my case–as though I was in high school muddling through my Spanish homework–constantly stopping to look up words  and rereading everything. N0w I like to think I have a basic fluency in breast cancer, but I also realize there is so much I don’t know.

When I was first diagnosed with metastatic breast cancer, I wanted to set the world on fire. I think I have calmed down a little bit. I hope I have become more focused.

Prior to my own diagnosis, I thought of breast cancer as one disease. I didn’t realize that the absence or presence of cell receptors--as determined by one’s pathology report–guide treatment as does HER2 status. (“The  tissue is the issue,” as my friend Marnie says.) Tumor characteristics ultimately determine what “kind” of breast cancer one has.

Most breast cancer can be categorized as follows:

  • ER/PR+; HER2- (accounts for 65% of breast cancer cases)
  • ER/PR+; HER2+ (accounts for 20%  of breast cancer cases)
  • ER/PR-; HER2-. (accounts for 15%  of breast cancer cases)

Update: A couple of readers with ER-/PR+ breast cancer noted that the above is a bit of an oversimplification.  Here is a further breakdown courtesy of BreastCancer.org :

  • ER+: About 80% of breast cancers are estrogen-receptor positive.
  • ER+/PR+: About 65% of estrogen-receptor-positive breast cancers are also progesterone-receptor-positive. This means that the cells have receptors for both hormones, which could be supporting the growth of the breast cancer.
  • ER+/PR-: About 13% of breast cancers are estrogen-receptor-positive and progesterone-receptor-negative. This means that estrogen, but not progesterone, may be supporting the growth and spread of the cancer cells.
  • ER-/PR+: About 2% of breast cancers are estrogen-receptor-negative and progesterone-receptor-positive. This means that the hormone progesterone is likely to support the growth of this cancer. Only a small number of breast cancers test negative for estrogen receptors but positive for progesterone receptors.
  • ER-/PR-: If the breast cancer cells do not have receptors for either hormone, the cancer is considered estrogen-receptor-negative and progesterone-receptor-negative (or “hormone-receptor-negative”). About 25% of breast cancers fit into this category.
  • HER2+: In about 25% of breast cancers,the HER2 gene doesn’t work correctly and makes too many copies of itself ( HER2 gene amplification). All these extra HER2 genes tell breast cells to make too many HER2 receptors (HER2 protein overexpression).

Also: If you are reading scientific papers, it’s helpful to know that researchers typically  divide breast cancer into four major molecular subtypes: Luminal A, Luminal B,  Triple negative/basal-like and HER2 type. Read a detailed explanation here.

Inflammatory breast cancer (IBC), the kind my mom had, refers to an unusual presentation–there’s no lump, the disease is generally found at Stage 3 or Stage 4. In general, IBC is first treated with chemo, followed by surgery and then radiation. Hormone receptor and HER2 status guides treatment–someone with IBC could have ER/PR+ HER2- breast cancer, for example.

I knew invasive ductal carcinoma (IDC)  (starts in ducts)  and is the most prevalent kind–it accounts for 50 to 75% of all invasive breast cancers. Invasive lobular carcinoma (ILC) (starts in milk glands, aka lobules)  is the next most common type, making up about 10 to 15% of all invasive breast cancers.  ILC generally does not have “lumps” like you’d find with IDC. Instead, ILC grows as sheets of cancerous cells–therefore it is harder to find via mammograms or self exam. 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.

I knew that breast cancer had stages and that Stage 4 wasn’t good. I didn’t realize that no one dies from early stage breast cancer–but that 20 to 30 percent of those with early stage breast cancer will go on to have a metastatic recurrence.

I did not know that a de novo presentation–someone who is metastatic from first diagnosis, is the exception rather than the rule. About 90% of those with metastatic breast cancer were previously treated for breast cancer; only 10% of us are metastatic from the start.

I did not realize that our US cancer registry does NOT track breast cancer recurrence–even though that is how most people join the metastatic breast cancer ranks. The NCI and SEER databases record only incidence, initial treatment and mortality data.  What happens in between — in terms of recurrence and the exact number of people living with metastatic breast cancer — is undocumented. As Musa Mayer says, ““It is as if these metastatic [people]  are invisible, that they literally don’t count. And when we don’t count people’s needs, we can’t provide or plan for them.”

I did not know breast cancer could spread to your bones, liver, lungs or brain. I knew it was bad if it spread beyond your lymph nodes.

I did not know that having the “worst” kind of breast cancer doesn’t necessarily mean you will have chemo right away. I assumed ALL cancer patients had chemo.  In my case, I will not have chemo until all of  the less toxic options have been tried first. This is both because of my cancer’s characteristics ( ER/PR+; HER2-);  and because my cancer remains under good control. Someone with triple-negative breast cancer can’t use  the anti-hormonal drugs (Tamoxfin; Femara, etc) that I do–their cancer would not respond (because it lack the necessary cell recpeptors).

I did not know having metastatic breast cancer means you are a patient for life. Or that the average patient may receive eight or 10 different treatment regimens in sequence. When one drug fails, you move on to the next one. Most people with MBC see their oncologist every month. If  the cancer is under good control, these appointments might be less frequent. But for most it is at least a monthly visit.

I did not know every three or four months I would have scans to see how well or  if my treatment was working. This is anxiety provoking and hard to understand if you have never experienced it.

I didn’t know my scan results could be categorized as No Evidence of Disease (NED), Stable (nothing got bigger or smaller, everything stayed the same); or Progression. I have never been NED but I have been stable, which is good, too.

I did not know that in some cases, people can live with metastatic breast cancer for a long time. I assumed everyone with metastatic breast cancer immediately got really sick and soon succumbed to the disease. While that does happen to some people, it is not universally true. Prognosis depends on many factors, including disease subtype and tempo.

I knew that not having children increases one’s risk for breast cancer, probably because of the unopposed flow of estrogen. I didn’t realize HAVING children increases a woman’s risk for breast cancer for about 10 years after giving birth. I would be willing to bet many women’s doctors either don’t know this or assume that this is a rare occurrence.

I assumed that being diagnosed with metastatic breast cancer at age 43 put me on the younger end of the MBC spectrum. I have sadly discovered this is not the case. I have met women in their 20s with metastatic breast cancer. While it is true that breast cancer is a disease of aging, I think members of the general public would be shocked to hear from some of these young people. Anecdotally, my experience is that there quite a few young women with MBC–too many, in any case.

I did not know that although breast cancer is diagnosed in far more white women, black women are far more likely to die of the disease.

I knew that men could get breast cancer but I  assumed this hardly ever happened. I have met (in person and online) at least five men with metastatic breast cancer. I am pretty sure these men and their families take scant comfort in the “rare” categorization.

I assumed that if one needed financial aid, one could merely call upon one of  the well-known cancer associations or national breast cancer groups. (Let me stress I am fortunate that I have not had to seek financial aid, but I know many who have.) I have learned that few national groups disburse funds. Typically one has to get help  from a local chapter or affiliate or community group and once those funds are gone for the year that’s it. I have learned most aid is fairly modest–getting help will require applying to many different sources.

I did not realize how poorly funded ALL metastatic cancer research is.

I did not know that a  drug that PREVENTS metastasis may not SHRINK a large, refractory tumor. It has a different mechanism of action that is NOT picked up by the clinical trial system. I did not realize some of our best metastatic researchers are advocating for a new approach to clinical trials.

I did not realize that most Breast Cancer Awareness Month coverage focuses almost exclusively on those with early stage disease. People are either afraid of our reality or prefer to ignore it in favor of  “feel-good” stories. Of course, we’ve also seen the other extreme–someone assuming ALL people living with MBC are on their deathbeds, which isn’t necessarily true either.

I did not know the  incidence of stage IV breast cancer—the cancer that is lethal—has stayed about the same; screening and improved treatment has not changed this.

I did not know breast cancer kills 40,000 annually in the US and half a million worldwide. Breast cancer remains the second leading cause of cancer death for women in the US, and it is the leading cause of cancer death for women globally.

Most of all, I did not know that there was so much that I did not know!

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