By BISHAL GYAWALI MD
Long list of news in lung cancer
September was an important month in oncology—especially for lung cancer. The World Conference in Lung Cancer (WCLC) 2018 gave us some important practice-changing results, also leading to four NEJM publications. The trial with most public health impact is unfortunately not published yet. It’s the NELSON trial that randomised more than 15000 asymptomatic people at high risk of lung cancer to either CT-based screening for lung cancer or to no screening and found a significant reduction in lung cancer mortality rates among the screened cohort compared with the control cohort. This reduction was more pronounced among women, although they constituted only 16% of the trial population. I am looking forward to reading the full publication and am particularly interested in knowing if there were any differences in all-cause mortality rates and the rates of overdiagnoses.
A new ALK-inhibitor on the block—brigatinib—has significantly improved PFS versus crizotinib when used as first-line therapy in ALK-positive non-small cell lung cancer (NSCLC) patients. However, I assume that it will be difficult for brigatinib to replace alectinib in this setting, since the latter has already been tested in two different RCTs and has more mature data.
With Keynote 407, pembrolizumab has entered into the treatment arsenal for squamous NSCLC by improving overall survival in combination with chemotherapy versus chemotherapy alone as a first-line regimen. However, when A B is compared with A, it is important to know whether A B is better than A followed by B. In this trial, 32% of patients who were in the control arm received a PD-1 inhibitor upon progression. Nivolumab is already approved as a second-line option in this setting after first-line chemo; so how much benefit in Keynote 407 is due to more than half of control arm patients not getting PD-1 inhibitor at all versus the benefit of combining pembrolizumab with chemo upfront is an important question.
It was 1970. I was in my laboratory at the NIH sequencing a murine myeloma protein in order to define the structure of its antibody combining region. Studies of protein conformation were at the cutting edge of science then; enthusiasm abounded. But it was clear to me that this work, in all its scientific elegance, had little to do with treating myeloma or anything else in mice or man. The reason for all the painstaking effort was the joy of pushing back the frontier of ignorance, even if only a bit. No one could foresee clinical utility then, nor would any become apparent for decades. Today such monoclonal antibodies are widely used to treat many diseases, sometimes with efficacy that justifies the costliness.
Genomics is in a bigger hurry.
Thanks to 40 years of breakthroughs, many earning Nobel Prizes, the chromosome carrying the defective gene underlying a genetic disease, Huntington’s disease, was identified in 1983 and the gene sequenced a decade later. In short order, defective genes underlying a number of single-gene diseases were defined: cystic fibrosis, hemophilia, and others. We all wait with baited breath for these elegant insights to transform into primary treatments for single allele genetic diseases. Attempts to transfect patients with normal genes are encouraging but barely so; it has proved difficult to get the right gene to stay in the right cells. Likewise, directly modifying the abnormal genetic apparatus is still largely just promising. The fallback remains working downstream from the genetic apparatus, replacing or modifying the defective products of many of these pathogenetic genes. Nonetheless, optimism regarding modifying the genetic apparatus itself is rational as is ever more boldness on the part of molecular biologists.
To the two certainties of life, death and taxes, add another two: mammograms and controversy surrounding mammograms.
The Canadian National Breast Screening Study (CNBSS) has reported results of its long term follow-up in the BMJ: no survival benefit of screening mammograms.
To paraphrase Yogi Berra “it’s mammography all over again.”
Is the science settled then?
Before I wade further it’s important to understand what is implied by “settling the science.”
Einstein said “no amount of experimentation can prove me right; a single experiment can prove me wrong.”In physical sciences a theory need only be disproven once for it to be cast aside. Heliocentricity cannot coexist with Ptolemy’s universe. The statement “all swans are white” is disproven by a single black swan.
What do we do with the studies that showed survival benefit of screening mammograms? Why does the CNBSS not close the debate over mammograms, like Galileo did with celestial egocentricity?
The simple and simplistic answer is because there are powerful advocacy groups, special interests; the pink-industrial complex who have a vested interest in undermining the science.
But that lends to conspiratorial thinking. Special interests cannot undermine Maxwell’s equations or Faraday’s laws just because they do not like them.
The testability of Maxwell’s equations is inherently different from verifying that screening mammograms increase life expectancy. We must acknowledge two types of science; the former, physical science, a hard science; the latter, a hybrid of biology and epidemiology, soft science.
Soft science is a misnomer. There is nothing soft about performing a randomized controlled trial (RCT), the methodological gold standard; in ensuring factors that falsely augment or attenuate impact of screening mammograms are evenly distributed, data reliably collected, cause of death accurately recorded and correctly inferred. But the human factor and all its inevitable foibles are unavoidable in soft sciences.
There is an old joke. What’s a radiologist’s favorite plant? The hedge.
Radiologists are famous for equivocating, or hedging.
“Pneumonia can’t be excluded, clinically correlate”. Or “probably a nutrient canal but a fracture can’t be excluded with absolute certainty, correlate with point tenderness”.
Disclaiming is satisfying neither for the radiologist nor the referring physician. It confuses rather than clarifies. So one wonders why legislators have decided to codify this singularly unclinical practice in the Breast Density Law.
The law requires radiologists to inform women that they have dense breasts on mammograms. So far so good.
The law then mandates that radiologists tell women with dense breast that they may still harbor a cancer and that further tests may be necessary.
You may quibble whether this disclaimer is an invitation or commandment for more tests, or just shared decision-making, the healthcare equivalent of consumer choice.
But it’s hard to see why any woman would forego supplementary tests such as breast ultrasound, magnetic resonance imaging and 3 D mammogram, or all three, when their anxiety level is driven off the scale.
What piece of incontrovertible evidence inspired this law, you ask?
Perhaps a multi-center trial run over 10-15 years that randomized women with dense breasts to (a) mammograms plus additional screening and (b) screening mammograms alone, show that additional screening saves lives, not just find lots of small inconsequential cancers.
No. The law was instigated by a heart-rending anecdote, which avalanched into the “breast density awareness” movement, cloaked by an element of scientific plausibility: women with dense breasts may have a higher incidence of cancer; a conjecture of considerable controversy.
Wasn’t the Affordable Care Act (ACA) supposed to usher an era of rational policy-making, guided by p values, statistics not anecdotes?
A preventive breast cancer vaccine developed by Professor Vincent Tuohy of the Cleveland Clinic will be brought forward to the FDA for permission to begin clinical trials to see if it is safe and effective for use in women.
The vaccine was shown to be completely safe and 100% effective in preventing breast cancer in three animal models, (see study in Nature Medicine), and was also found to slow the growth of tumors that had already formed. The vaccine is especially powerful in inhibiting the growth of triple-negative breast cancer, the most aggressive form of the disease with the lowest survival rate.
Triple-negative breast cancer lacks estrogen, progesterone and Her2 receptors. It occurs in approximately 15% of cases is the kind of breast cancer most common in women who carry a BRCA mutation.
The initial clinical trials, called Phase I studies, will be conducted in two groups of volunteers, women with triple-negative breast cancer who have completed their treatment and are free of disease, and women who will be vaccinated shortly before undergoing bilateral prophylactic mastectomy (typically these are women like Angelina Jolie with BRCA mutations who elect to remove their breasts to lower their risk for cancer.)
The first group of women will be studied to determine the dose and effectiveness of the vaccine; the second will be studied to make sure the vaccine does not trigger an untoward immune response in breast tissue.
The vaccine targets an unique protein normally made only by women who are breastfeeding, alpha lactalbumin (ALA). In the 12 years Tuohy spent developing and researching his vaccine, he discovered that the majority of breast tumors express, or make, ALA. Priming the immune system with a vaccine so that it attacks any cell that makes ALA is the method by which Tuohy’s vaccine works.
Because the vaccine targets ALA, a protein necessary for successful lactation in healthy women, the vaccine would not be appropriate for use in women who are still in their childbearing years.
However, the majority of women diagnosed with breast cancer in the United States and other western countries are post-menopausal: at least 60% of the cases in the United States occur in women over 55; thus, Tuohy’s vaccine holds great potential as a preventive vaccine for the majority of women.
Dear Ms. Jolie,
Thank you for your bravery and leadership in the battle against breast cancer. In a small way, through my patients, I understand the challenge and pain it took not only to undergo prophylactic mastectomies, because you carry the BRCA1 cancer gene, but also to reveal this deeply personal part of your life to the world (NYT, 5/14/13; My Medical Choice). You had no obligation to open your soul; your selfless act leaves those of us that treat the dread disease, in awe.
Your action will save more lives than all the patients I could help, even if I were to practice oncology for hundreds of years. By opening up the conversation, by educating and by boldly stating that beauty, strength and health are possible, even when radical choices are made, you open up life saving opportunities for many. Mastectomies may not be the answer for all women, but the very idea that cancer can be prevented, instead of simply waiting in fear, is earth shattering.
Women and men will now better understand the genetic risks for cancer, be exposed to the different options which are available in the prevention of cancer and know that it is possible, whatever path is taken, to continue with full lives. You have made it easier for patients, their families and physicians to have vital discussions.
The announcement of your surgery coincides with a critical legal battle, the deliberations of the United States Supreme Court regarding BRCA genetic testing. You have put pressure on the Court to find against Myriad Genetics Corporation in the company’s attempt to protect their expensive monopoly of the breast cancer genetic assay. Thus, the Court will have the opportunity to reduce the cost of testing, which as you note, can run thousands of dollars per patient.
Your action changes the war against breast cancer. You have prevented the suffering of thousands and given them the opportunity to go on with life and be part of what is truly important, families and communities.
Thank you for your remarkable sacrifice.
James C. Salwitz, MD
James C. Salwitz, MD is a Medical Oncologist in private practice for 25 years, and a Clinical Professor at Robert Wood Johnson Medical School. He frequently lectures at the Medical School and in the community on topics related to cancer care, Hospice and Palliative Medicine. Dr. Salwitz blogs at Sunrise Rounds in order to help provide an understanding of cancer.
A woman’s mother dies at age 56. A blood test is done. The woman finds out she has a genetic pre-disposition to cancer. She takes what action she thinks she needs to take. A familiar story repeated over and over again every day. I’ve met many women who have made this choice. While not “normal”, it is a familiar situation. These women’s difficult choices go unheralded. But not Angelina. She has a voice and she’s not afraid to use it.
I am of two minds about Ms. Jolie’s announcement. Unlike double mastectomies for ductal carcinoma in situ (DCIS), which isn’t necessarily a cancer and can be treated with a lumpectomy, BRCA1 gene mutations can’t be treated any other way. Unless I hear differently from my breast surgeon friends, I’d say she probably did the right thing. Her decision to talk about it is probably encouraging to women who have or will have to make that choice. It raises awareness of the gene mutation. It puts breast cancer on the front page of the New York Times. Again.
Here’s my problem: double mastectomy is not a benign procedure. Ms. Jolie seems to have had a remarkably easy time of it. Yes, she says she was right back to her normal life soon after, but since Jolie’s life is not normal that’s hard to generalize. The truth is there is significant pain involved, a long period of waiting while the tissue expanders do their work, then there’s further procedures for the implants, which can develop capsules around them, or rupture, or get infected. If Angelina had chosen breast reconstructive surgery there would be the risk of the flap losing blood flow, multiple drains, overnight stays in recovery rooms or ICUs, and many many surgeries for revision, nipple creation, etc. And the results are not always beautiful. I understand that it is not Ms. Jolie’s role to scare people, but to encourage them. I would just warn against falsely rosy expectations.
I am not trying to discourage double mastectomy. Sometimes it is necessary. I do think that people who have extraordinary access to public attention must pay extraordinary attention to what they say. I wish Angelina all the best for a complete, and beautiful, recovery.
Shirie Leng, MD is a practicing anesthesiologist at Beth Israel Deaconess Medical Center in Boston. She blogs regularly at medicine for real.
The passage of the Affordable Care Act (Obamacare) and the reelection of President Obama was cause for real hope among those in pursuit of the Holy Grail in medicine: higher quality at lower cost. However, with the passage of what is called the Breast Density Bill in several states, the quality cost equation seems doomed on both ends. The Affordable Care Act mandates coverage of screening mammograms, without co-pay or deductible, but the Breast Density Bill is destined to push utilization of “non-beneficial” imaging, ie imaging that does not clearly save lives, even further.
The new law, authored by Sen. Joe Simitian, was signed into law this past October in California. Beginning April of next year, the bill requires facilities that perform mammograms to include a special notice, within the imaging report sent to patients, regarding the high density of breast tissue and the benefit of additional screening tests. The notice will state the following; “Because your mammogram demonstrates that you have dense breast tissue, which could hide small abnormalities, you might benefit from supplementary screening tests, depending on your individual risk factors”.
The supporters of the bill make the ethical argument that women have the right to know about how dense breast tissue can obscure mammogram visualization, and should be offered additional test such as ultrasound and magnetic resonance imaging (MRI) to alleviate the doubt. To provide further support, the SOMO INSIGHT Breast Cancer Screening Study is a nationwide research effort to evaluate if automated breast ultrasound done together with routine screening mammogram is more accurate in detecting breast cancer in women with dense breast tissue. The study is funded by U-Systems, Inc.; the Silicon Valley based company responsible for the sophisticated and expensive ultrasound technology used in this study. Thus, one cannot deny the possibility of patient interest being confounded by financial interest.
The patient advocacy movement around breast cancer has been championed by several well-known non-profits, such as Susan B Komen, Are You Dense Inc. and even endorsement by the National Football League. Yet, the confusion about screening is reflected in the variability of requirements for insurance coverage between states. For example, while Texas and Mississippi require screening mammograms to be covered for all women 35 and older, Utah has no coverage requirement and several other states do not require coverage until age 40.1 Awareness of breast cancer screening is necessary, and the complexities of picking up certain irregularities certainly deserve attention. However, the patient’s “right to know” should also include the right to know about “over-diagnosis”.
For those of you who haven’t yet heard, I have recently been diagnosed with Stage IV inflammatory breast cancer. This rare form of breast cancer is known for its rapid spread. True to form, it has metastasized to my spine. This means my time is limited. As a nurse, I knew it from the moment I saw a reddened spot on my breast and recognized it for what it was.
My recent journey through the health care system has been eye-opening. In only a few months, I have witnessed the remarkable capabilities and the stunning shortcomings of our health care system firsthand. I am writing here because in the time I have left, I hope my story and my journey can help illustrate why some of the reforms that my colleagues and I at the John A. Hartford Foundation, as well as many others, have championed are so important.
At the cancer’s earliest appearance, I consulted with a well-regarded oncologist in New York. After the tests were done she regretfully informed me that my disease was not curable. Because my cancer is hormone-receptor-positive, she recommended an evidence-based course of medications aimed at slowing the progression of the disease. Before I committed to this course of care, I wanted to get a second opinion. I secured an appointment with the pre-eminent researcher/clinician in the field of inflammatory breast cancer, at a top medical institution in Philadelphia.
Not to be overly dramatic, but for me the Supreme Court decision on the Affordable Care Act was a matter of life and death. Because the law was largely upheld, I will be able to continue receiving treatment for breast cancer.
I was one of the early beneficiaries of the law. When I was diagnosed with an aggressive form of breast cancer late last year, I had no health insurance, which meant my options were extremely limited. No insurer would pick up someone in my circumstances. But luckily, the Pre-existing Condition Insurance Plan had already kicked in, and it made it possible for me to purchase insurance under a government program.
I was uninsured not because I’m a lazy, freeloading deadbeat but because my husband and I are self-employed. We had been purchasing health insurance on the individual market along with 6% of the rest of the population. But after exhausting all of our resources trying to keep up with premiums of $1,500 a month, we had no choice but to cancel it.