Wednesday, June 14, 2017

Immunotherapy Trials Encouraging for Metastatic TNBC

The first triple negative breast cancer immunotherapy trial to date has yielded some hopeful results for metastatic TNBC, according to results presented at the 2017 American Society of Clinical Oncology Annual Meeting.
The checkpoint-blocking drug Keytruda shrank pre-treated tumors by more than 30 percent in 5 percent and stabilized disease in 21 percent of women in the group. All patients who saw their tumors shrink lived for at least another year. In comparison, the patients who did not experience tumor regression had lower survival rates. (Remember: This is metastatic TNBC, or stage 4, not earlier, or more treatable, forms, such as stages 1-3.)
The trial included two groups of patients with metastatic TNBC. The first consisted of 170 patients who had received earlier chemotherapy. The second group was previously untreated and had tumors expressing the checkpoint molecule PD-L1.
Both groups tolerated the treatment well, with 12 percent of patients in the first group, and 8 percent in the second group reporting side effects such as fatigue and nausea. Four percent of patients in the first group, but none in the second, stopped the treatment because of these effects.

Monday, April 24, 2017

Radiation Recall? A Search for What Caused My Chest Inflammation After A Mastectomy

More than ten years after I had radiation on my breast, I developed a skin inflammation on the radiated site. It came on suddenly, a series of angry red veins branching across my chest where my left breast had been, with occasional darker, pooled spots, all in a rectangular shape matching the area where I had been radiated. My skin was smooth, with no bumps or lumps.

It was November 2016, a year and a half after my second bout of triple-negative breast cancer. My cancer story in a nutshell: I have had TNBC twice: once in 2006 and once in 2015. The second was not a recurrence, but a second primary cancer. For the first cancer, I had a lumpectomy, chemo, and radiation. The second time, with a tumor less than half a centimeter, I had a double mastectomy without reconstruction.

I had absolutely no problems with radiation burns while undergoing my original treatment, nor in the intervening ten years, although I do think it highly possible radiation was one cause of my second cancer.

The mastectomy, though, did not go all that smoothly. I developed seromas for months afterward, the last one being essentially a blood-filled bruise. The surgeon drained it and, within days, it had healed, but for a few days, the skin looked a little like the inflammation I was now seeing. At that time, my surgeon said the skin was weakened by the long-ago radiation and became even more damaged by the more recent surgery.

I went for a year after that last seroma with what might be considered normal healing after a mastectomy: some arm and incision pain, but nothing unusual. Now something was up. But what?

Radiation Recall

After checking online, I self-diagnosed radiation recall, which can occur years after radiation. Most cases are drug-related, caused when patients are given cancer-fighting drugs such as anthracyclines like adriamycin, after radiation. I had been given adriamycin, but that was ten years ago. Why would I now be having a reaction? It had to be something else. Chat rooms were full of discussions of women with radiation recall, with causes all over the board: scented lotions, wool, new prescriptions or over-the-counter drugs. Treatments were equally varied: antihistamines, steroid creams, and anti-inflammatory drugs such as ibuprofen.

Some mentioned that chest inflammation could be lymphedema of the trunk, which made a little sense, as my case was accompanied by pain in my upper arm. But mine was milder than those I saw online. I had none of the swelling that was indicative of lymphedema. 

The basic message from my research, though, was encouraging: Radiation recall is not usually a sign of a new cancer and is most likely a skin issue, some form of dermatitis.

My inflammation looked far, far better than photos I saw online, which showed chests that were completely red, often scaly. Mine looked modest in comparison. The closest was this one, which they call photo recall. Most other images made me thank my lucky stars.

As I was trying to figure this all out, a friend who is 11 years past her TNBC diagnosis messaged me and said that she has been diagnosed with radiation fibrosis. So I researched that, but I had none of the scarring that is characteristic of that syndrome. Still, it is a late effect for some breast cancer patients and seems worse for head, neck and throat cancer patients. Interestingly, a University of Iowa clinical trial recommended Vitamin E for radiation fibrosis, but vitamin E turned my skin red every time. That was one of the few direct effects I could see, and it ran contrary to much of what I read in general about soothing breasts to help them heal after surgery and to reduce radiation effects.

At the same time my chest got inflamed, I had throat phlegm that would not clear up and I remembered my friend Marilyn, who thought she had bad allergies but ended up having a recurrence of TNBC on her chest wall. I decided that was what was happening to me—the phlegm, as in Marilyn’s case, was an indication of a tumor, and the skin inflammation was just verification. Clearly, I was dying, because that is the conclusion we reach in these situations, right?  But I went to my primary care doctor for a professional assessment, just to be sure.

By the day of my appointment, the inflammation had almost disappeared—only a couple inflamed veins remained. The doc had to use a flashlight to see the reddened veins and was, not surprisingly, skeptical of my worries. As for the phlegm, she looked down my throat with a scope and felt my lymph nodes. Nothing again.  

“Could this be stress?” I asked her. This happened right after the election and I am a Democrat, so stress is my best buddy these days. “If you want it to be,” she answered. I mentally put that on my list of Obnoxious Things Doctors Have Said To Me.

But she told me that if that inflammation got worse or if the throat didn't get better in two weeks, to come back.

The next day, the skin got redder, but rather than heading back to the doctor, I began a diary of possible causes. The phlegm soon disappeared, so my focus returned to my skin, to this being a dermatological issue.

Searching For a Cause

I had worn a wool sweater the day the inflammation came on, with a nylon camisole underneath. That seemed like an obvious cause, so I stopped wearing any synthetics and used only cotton. I have worse only cotton in the five months since then. No real change, although the inflammation gets better for a bit, then worse again.

I use organic, unscented laundry soap, but I changed brands. No help.

I tried steroid creams and ibuprofen but noted no obvious cause and effect. I upped my dose of antihistamines. Nothing, except I got pretty sleepy.

I began to suspect some of the supplements I was taking, including a new multivitamin I began using the day after all this happened. Why it would have caused anything the day before I started it makes no sense, but I stopped it anyway. I even moderated my yoga, as it often hurts my affected arm and I thought maybe that could be related to the rash. So I cut out anything that put pressure on the arm. 

Again, the inflammation got better, then it got worse, and I could not determine any common factors. I concluded that it must be a mix of causes, some sort of perfect biological storm.

Then, I got a series of bumps along my incision. One was about a quarter of an inch in diameter. Again, I was clearly dying. If cancer recurs, it often comes as a rash at the incision site. This time, I made an appointment with my surgeon. But, by the time that appointment came, the bumps had shrunk and the inflammation as a whole had greatly reduced.

He came in somber-faced and I tried to tell him I was sure I had overreacted, but he wanted to go over my entire medical history before he looked at the rash. I was there with a recurrence, he thought, and that was not good news. Once he saw my chest, though, he smiled and said the bumps were clearly not tumors. Nevertheless, he wanted me to get a chest x-ray. More radiation? I asked. Low doses, he said. He wanted to make sure this had not spread to my lungs. Reluctantly, I agreed, acknowledging that by deciding to go to the surgeon in the first place, I at least subconsciously wanted the kind of answer that additional tests would give.

He called me the next day—my lungs were clear, except for the signs of COPD, which I knew I had. No tumors.

That day, the skin bloomed a bright purple again. A reaction to the x-ray? Who knows, but it’s hard to discount that possibility. But it healed a bit, then bloomed bright and angry again. So I went back to my diary, back to trying to figure out what was going on with my blasted chest.

I began to suspect the tonic water in my nightly gin and tonic, a drink I know I am better off without, so I cut it out and replaced it with healthier black cherry juice without gin. The rash again got better, then worse. There just seemed no pattern.

Three weeks after seeing the surgeon, I had my yearly appointment with the dermatologist. He looked at the inflammation, said it was probably harmless irritation, but took a biopsy nevertheless. Again, I was annoyed at the extra testing, but equally curious to see what it would show. The result: my skin was inflamed, but there were no signs of cancer. The pathologists suggested the inflammation was caused by a new drug or by contact with an allergen of some sort.

So, three doctors, an x-ray, and a biopsy later, I was right back where I was with my original Google search. This was likely caused by something I had injected or exposed my skin to. Except for one thing: after the biopsy, the rash cleared up almost entirely. More than ever before. Now, three weeks later, it is still mostly clear—just a few faint lines remain, but those might always be there. Gone are the red veins, the purple pools.


A Partial Answer

After the biopsy, I was advised not to shower that area—I had to gently clean it with a cloth. No hot water flowing over it. So, my dermatologist might have accidentally solved at least part of my mystery. I had been taking long showers to alleviate my stress after the election and, if all that hot water wasn't the cause, it was certainly exacerbating my inflammation. I’ve cut down on my showers, which is an environmentally kind thing to do in the first place. And my chest now looks almost normal, in the context of chests that have been radiated, deflated, and deformed. 

Eventually, perhaps, I will reintroduce some of the elements—my multivitamins, yoga arm exercises, tonic water—bit by bit and see what happens. Maybe I will eventually figure out what caused this, and maybe eventually my skin will be completely clear and this will all be a weird memory. What is obvious is that docs have no idea.

And right now, the only dark marks on my chest are the two spots where the doc took the biopsy. But even they are healing nicely.

Mystery unsolved, except there are no signs of cancer. And that, as always, is a good thing.

Wednesday, April 19, 2017

Cancer Professionals and Patients Anxious About Changes in Obamacare

Oncology professionals are concerned about the ability of their patients to access cancer screening and treatment under the American Health Care Act proposed by House Speaker Paul Ryan, according to a survey conducted in March at the National Comprehensive Cancer Network’s  Annual Conference.

A majority of those surveyed believed that anticipated changes to the Patient Protection and Affordable Care Act (Obamacare) would have a negative impact on their practices and on cancer research. More than 70 percent noted that patients have voiced concern about the anticipated repeal and replacement of Obamacare, nearly two-thirds of whom have demonstrated increased levels of distress.

The survey was conducted during the period of congressional debate over the American Health Care Act (AHCA), which was withdrawn the afternoon of March 24 when it became clear there were not enough votes to pass the legislation. Responding to the survey were 76 oncology professionals, including physicians, academic and community; nurses; physician assistants; pharmacists; industry professionals; payers and patient advocates. Republicans in the House continue to discuss ways to repeal or change the law.

“The American Health Care Act is tabled and the ACA remains in place, but concerns about access to cancer screening, care, and research funding remain. Today, patients are in limbo, not knowing what action the federal and state governments will take,” said Robert W. Carlson, MD, Chief Executive Officer of NCCN. “NCCN agrees there are ways to improve the current health care system for Americans with cancer, the clinical professionals who care for them, and payers. However, we are concerned for Americans with cancer that affordability, coverage of products and services in cancer treatment, and overall access will be impeded by allowing health insurers to set their own rates, or by providing states the ability to experiment with Medicaid coverage, without appropriate patient protections.”

The NCCN survey found:

Fifty-five percent of respondents reported that the anticipated large-scale changes to federal health care policy would likely have a negative impact on their practice, research programs or patient outcomes. Eleven percent anticipated a positive impact, and 34 percent anticipated a neutral, or mixed impact.
  When asked to select from a list of outcomes they anticipated would occur with changes to health care policy, those who anticipated a negative impact (55%) indicated:                         
   Fewer patients will have access to health insurance (71%)  High deductibles will limit patient access to care (69%)  Cancer screening rates will decline due to higher co-pays and deductibles (63%)  Patients’ pre-existing conditions could be excluded from coverage (57%)  Federal funding for cancer research will decline (56%)  There will be less support for mental health services (50%)
Those who expected a positive impact (11%) indicated:
   With increased competition for insurers operating across state lines, health insurance premiums and co-pays will go down for more patients, leading to improved access to care (50%)  Allowing medications to be imported will create more competition and reduced drug prices (50%)  Patient health savings accounts will lead to increased price transparency for medical procedures and medications, causing health care costs to drop (38%)
  When asked, “What kind of impact do you believe changes in federal health care policy will have on your patients’ ability to afford cancer care?” 66 percent of respondents said the impact would be negative; nine percent said positive; and 25 percent said the impact would be neutral.

   And, to the question, “To your knowledge, are your patients affected by health insurance policy and the possible repeal and replacement of the Affordable Care Act?” respondents answered:   
 Yes, patients have expressed concern and demonstrated greater levels of distress (50%)  Yes, patients have expressed concern but no evidence of health impact (21%)  No, I have not seen any effects (29%) 
“President Trump included three key elements in his approach to health coverage reform: repairing necessary aspects of the ACA, ensuring greater access, and lowering the total cost of care,” Dr. Carlson said. “We are ready to share our Network’s expertise with lawmakers to deliver a value-based health policy to ensure that all Americans with cancer have access to high-quality, effective, and efficient cancer care.”

Read Dr. Carlson’s March 21, 2017 letter to Congress outlining NCCN’s concerns about the health policy proposal and patient access to care here.

Information from a news release provided by the National Comprehensive Cancer Network.

Wednesday, October 26, 2016

I Didn't Expect It To Feel Like This

My nephew had been struggling with a diseased foot for more than a year—it got infected and did not heal, likely a consequence of his type 1diabetes. He will have to have his leg amputated, a step that stunned the entire family. In discussing his concerns, my sister told me that he doesn't want his leg to just be cut off and thrown into the trash.

“That’s what they did with my breasts,” I said. “Cut them off and threw them away.”

Hearing this, the rest of the family was silent, sort of struck by my vehemence. I seldom give details about my breast cancer treatment—living through it once was enough—so this surprised us all. Me most of all.

I had no idea of the anger I had suppressed beneath a cheery I’ve-got-this exterior. And to have it come out so melodramatically and inappropriately—this was about Rod, not me—was embarrassing. But that’s the case with repressed anger. It doesn't go away; it just builds and eventually spews itself like a verbal volcano, scorching all in its path.

So we returned to Rod’s issue, and our hope that he could soon have surgery and that he would respond well. A month ago, doctors amputated his leg beneath the knee and he is healing well. He’ll be measured for a prosthesis in a few weeks.

Meanwhile, there’s me and my breasts in a surgical landfill somewhere.

My double mastectomy was the result of a second bout of triple-negative breast cancer. I had successfully recovered from my first round, in 2006, and was looking forward to celebrating ten years cancer-free. So I was more angered than anything when the beast roared its nasty head in the same breast in 2015, nine years almost to the day of my first diagnosis. The second cancer was small, but I easily opted for a double mastectomy, wishing I had done that the first time—just sliced the darn things off.

I didn't expect it to feel like this. Even after nine years of working with breast cancer patients, corresponding with hundreds, writing a book and scores of articles and starting a well-regarded cancer blog.

I look in the mirror and see a disfigured woman looking back. My surgery looks like hell, frankly. I have extra, uneven flaps on the bottoms and side of both former breasts. If I don't wear my prosthesis, these bumps show through my shirt, looking like tiny mole tunnels popping through my chest wall. A friend, who is a breast cancer surgeon and survivor, says this type of result frustrates doctors. The problem: docs operate on a woman while she is lying down and end up with a chest that is nice and even and flat and clean. But when the woman stands up, gravity takes over and packets of fat appear. These are not remainders of the breasts, but fat tissue that had surrounded them. Multiple docs have checked my surgical site and all is supposedly well—it’s healing as it is supposed to, and it falls within the fairly wide spectrum of normal. It just looks awful.

My surgical scars don't line up, probably because I'd already had a lumpectomy in my left breast. I see photos of women who have cool tattoos on their breasts and who proudly go flat, but they actually are flat, with a clear surgical line across their chests, not a jagged barbed-wire looking strip.

Of course, I could have plastic surgery to smooth things out, but I don't want more operations and more recuperation and more stuff added to my body. I do wish I’d had a plastic surgeon involved with surgery in the first place. But I now have much better understanding of why other women choose that route, especially younger women. I always got this intellectually, but now I get it emotionally.

I have several decent prostheses—a fancy gel-filled one that looks like a creature that washed up on a beach, a lighter foam set, and a cotton-filled number. The creature looks the best on, but the cotton one feels best. And I notice that, in photos, my body looks pretty trim and tight, with the kind of firm breasts you don't normally see on a 70-year-old. So whoop.

I feel great and continue to walk two miles a day and hike in the summer at our Colorado cabin. I’m writing another book and painting again and enjoying my family. My husband and I travel a lot and just enjoy one another in our down times.

So life, really, is good. And if Rod can move on after losing a leg that is essential to his mobility, I can be just fine losing breasts and having a chest that looks like a mistake.

Still, I retain the right to be grumpy.

Thursday, May 12, 2016

New Target for TNBC Found, Say UC Berkeley Researchers

University of California, Berkeley researchers have found a long-elusive Achilles’ heel within “triple-negative” breast tumors, a common type of breast cancer that is difficult to treat. The scientists then used a drug-like molecule to successfully target this vulnerability, killing cancer cells in the lab and shrinking tumors in mice.

“We were looking for targets that drive cancer metabolism in triple-negative breast cancer, and we found one that was very specific to this type of cancer,” said Daniel K. Nomura, an associate professor of chemistry and of nutritional sciences and toxicology at UC Berkeley and senior author for the study, which is published online ahead of print on May 12 in Cell Chemical Biology.

Triple-negative breast cancers account for about one in five breast cancers, and they are [Pat's edit: "they may be"] deadlier than other forms of breast cancer, in part because no drugs have been developed to specifically target these tumors
Triple-negative breast cancers do not rely on the hormones estrogen and progesterone for growth, nor on human epidermal growth factor receptor 2 (HER2). Because they do not depend on these three targets, they are not vulnerable to modern hormonal therapies or to the HER2-targeted drug Herceptin (trastuzumab). 

Instead, oncologists treat triple-negative breast cancer with older chemotherapies that target all dividing cells. If triple-negative breast cancer spreads beyond the breast to distant sites within the body, an event called metastasis, there are few treatment options.

Tumor cells develop abnormal metabolism, which they rely on to get the energy boost they need to fuel their rapid growth. In their new study, the research team used an innovative approach to search for active enzymes that triple-negative breast cancers use differently for metabolism in comparison to other cells and even other tumors. 

Inhibiting cancer metabolism
They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

Co-author Eranthie Weerapana, an associate professor of chemistry at Boston College, developed a molecule named LAS17 that tightly and irreversibly attaches to the target site on the GSTP1 molecule. By binding tightly to GSTP1, LAS17 inhibits activity of the enzyme. The researchers found that LAS17 was highly specific for GSTP1, and did not attach to other proteins in cells.

According to Nomura, LAS17 did not appear to have toxic side effects in mice, where it shrank tumors grown to an invasive stage from surgically transplanted, human, triple-negative breast cancer cells that had long been maintained in lab cultures.

The research team intends to continue studying LAS17, Nomura said, with the next step being to study tumor tissue resected from human triple-negative breast cancers and transplanted directly into mice. 

“Inhibiting GSTP1 impairs glycolytic metabolism,” Nomura said. “More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells.”

Beyond the metabolic role they first sought to track down, GSTP1 also appears to aid signaling within triple-negative breast cancer cells, helping to spur tumor growth, the researchers found.

Technique identifies Achilles' heels
Nomura said it was surprising that a single, unique target emerged from the research team’s search. 
The method used by the researchers, called “reactivity-based chemoproteomics,” can quickly lead to specific targetable sites — the Achilles’ heels — on proteins of interest, and eventually to drug development strategies, Nomura said.

The approach is to search for protein targets that are actively functioning within cells, instead of first using the well-trod path of surveying all genes to identify the specific genes that have taken the first step toward protein production. With that more conventional strategy, the switching on, or “expression,” of genes is evidenced by the easily quantified molecule called messenger RNA, made by the cell from a gene’s DNA template.
Nomura’s team instead first used chemical probes that can react with certain configurations of two of the amino acid building blocks of protein — cysteine and lysine — known to be involved in several kinds of important structural and functional transitions that active proteins can undergo.

 “A lot can happen after the first step in protein production, and we believe our method for identifying fully formed, active proteins is more useful for tracking down relevant differences in cellular physiology,” Nomura said.
The researchers analyzed and compared cells from five distinct triple-negative breast cancers that had been grown in cell cultures for generations, along with cells from four distinct breast cancers that were not triple negative. 

The scientists used a chemical identification technique known as mass spectrometry to narrow down the set of proteins that had active lysines and cysteines to just those that were metabolic enzymes. Only then did they use the more conventional approach of measuring gene expression in the different cancer cell types.

GSTP1 was the only metabolically active enzyme that was specifically expressed only in triple-negative breast cancer cells compared to other breast cancer cell types, the researchers found. Separate analysis of databases of human breast cancer by UC San Francisco co-authors confirmed that GSTP1 is overexpressed in patients with triple-negative breast cancers in comparison to patients with other breast cancers.