The Internal Enemy | Raising-action

Providing information to the patient 

(Fictional narrative by the doctor)

James Fleck, MD, PhD & João A de Andrade, MD

Anticancerweb 31 (12), 2018

I spent two days preparing an education packet to address Ruth's request. I felt that this information could also be very useful to other patients, although none of them never clearly expressed the desire to know the "internal enemy” in depth as Ruth had! 

I was not completely sure how detailed the information should be. I eventually decided to draft a very broad document that contained a number of important general principles:

Exploring cancer is akin to having a glimpse of all the laws of physics in action just by looking at the sky. The difference lies on size of the particles. Cancer biology is based on a miniaturized world that goes way beyond the optic microscopy, reaching the molecular universe.

The human body is made up by cells. Cell arrangements compose the tissues, whose associations produce the different organs. The expression of cell form and function is determined by genes. Genes are DNA segments neatly organized within chromosomes that reside in the nucleus of each cell. 

Our body’s first cell is the result of fertilization. From that moment on, all chromosomes get into action, and multiple genes progressively guide the fetal development. Once the body is completed and the child is born, important changes begin to occur. Only 10% of the genes originally present in the human genome remain active. Consequently, the genes that directed cell proliferation and differentiation in uterus become inactive within our cells, following a precise biological program. The keys that turn genes on and off work automatically at different stages of our development. The so called “oncogenes” are essentially genes related to cell proliferation that “wake up” as part of a pathological process that lead to the development of cancer. 

In summary, cancer arises when there is a significant abnormality in the dynamics of the genetic cellular programming that shifts the biological processes towards disorganized proliferation.

We are often victims of physical, chemical, and biological insults on nuclear DNA, which might affect the systems that control gene expression. These insults may lead to the activation of the above mentioned “sleeping oncogenes”, increasing the number of copies and promoting gene amplification. On the other hand, nature controls the instability of our DNA through tumor suppressor genes. They are continuously repairing DNA damages, thereby preventing the arise of an abnormal (i.e. cancerous) cell population.In other words, a DNA mutation caused by a given insult may either promote oncogene amplification or the loss of a gene suppression function, starting a process that will lead to the appearance of cancer cells.  

Cancer cells are very smart and soon acquire immortality. There is a terminal region in our chromosomes called telomere, which control a cell’s lifespan. The size of the telomere is responsible for apoptosis, which is also called “programmed cell death”. The progressive shortening of the telomere is responsible for our finitude. An enzyme called telomerase works to maintain the telomere length, which promotes the undesirable immortality of tumor cells. In fact, the 2009 Nobel Prize in Medicine was shared by three American researchers: Dr. Blackburn at the University of California, Dr. Greider of Johns Hopkins University and Dr. Szostak of Harvard University. They reported that cancer cells had an increased expression of telomerase.

The Cancer Genome Atlas is a major ongoing comprehensive international effort to describe the patterns of genetic mutations for each tumor cell type. We can now envision new routes of therapies that are more efficient and personalized. Many of these studies were summarized in a series of articles published by the medical journal Nature in 2013. The transfer of this knowledge to clinical practice is the goal of Translational Medicine and some of these advances have already been incorporated in our daily workflow. Treatments are now more customized, combining new targeted therapies with advanced surgical techniques, chemotherapy and radiation therapy. Gradually, Medicine is expanding its arsenal of weapons against the internal enemy.

Despite an apparent disorganized growth, cancer cells function as a fine-tuned orchestra. Genetic and epigenetic alterations interfere in normal cellular signal transduction pathways, dysregulating cell proliferation and microenvironmental interactions such as motility and angiogenesis, leading to tumor progression. These changes usually involve binding of signaling molecules (ligands) to specific receptors causing structural changes and hyperactivation of the signal transduction pathway. Growth factors’ receptors play an important role in the cancer signaling cascade. Around 20% of breast cancer cells have increased expression of the Her-2 gene. Her-2 overexpression might reach up two million receptors per cell, triggering multiple downstream transduction signals, which are responsible for breast cancer cell over-proliferation. Fortunately, nowadays we have a number of drugs that are able to block multiple levels of the signaling transduction pathways.

A comprehensive view of both the cellular microenvironment and the molecular network of communication (signaling transduction pathways) allows for one to understand why cancer diagnosis ought to be established at both histological and molecular levels. A biopsy and the histopathologic diagnosis alone are no longer enough. Additional tests that include immunohistochemistry and gene amplification provide a much broader and personalized evaluation of the phenotypic expression of the tumor cells.

The intriguing behavior of cancer cells is partially explained by a high mutation rate. Mutations are responsible for the cancer cells’ over-proliferative state, local invasion and, ultimately metastatic disease. All these aggressive features are magnified by a tumor-induced suppression of the immune system’s natural ability to recognize cancer cells. In 2018, the Nobel Prize in Medicine was awarded to the researchers James Allison of the University of Texas and Tasuku Honjo of Kyoto University for the identification of the “immunological checkpoints”. The main players are the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), the programmed death-1 (PD-1) and its ligand PD-L1. These are regulators of the cellular immune function that paralyze the immune response against tumor cells. Many cancer cells expose the PD-L1 binding protein which, when attached to the PD-1 receptor on the lymphocyte, allows the cancer cells to evade the inhibited immune system and continue to proliferate and migrate.This concept has been successfully used in the treatment of immunogenic tumors such as melanoma and lung cancer. Monoclonal antibodies against CTLA-4, PD-1 and PD-L1 have been developed in an attempt to restore or activate tumor cell immunological recognition with very promising results.

Before sending it to the patient, I went through several drafts to ensure clarity while avoiding oversimplification. It was the first time I wrote educational materials at patient’s behest. I must admit that I had mixed feelings. Was I doing the right thing? How would it be received? How understandable would it be? Could it cause harm? 

I could simply ignore Ruth's request for more information and stay within my comfort zone by just giving strict technical advice. I could also play down the seriousness of the disease as a way to come across as a more compassionate physician.  However, both approaches seemed highly inadequate for someone who cleverly declared cancer to be her "internal enemy”.

After a while, I decided that it would be best to send the final draft to her via e-mail.

I waited for a reply, which did not happen immediately.

After three days, I was very concerned. One of the main principles in Medicine is primum non nocere, which means “first do no harm”. I was afraid that I had caused some emotional distress by providing so much information. Fortunately, on the fourth day, her reply finally arrived!

She began by thanking me for sending all the information. She was satisfied with the package, which she felt was very useful, albeit very technical. She felt better prepared and more confident to face her "internal enemy". She also mentioned that she felt that the doctors did not seem to be afraid of cancer any longer, since they already knew how successfully treat it. However, what impressed me the most was when Ruth wrote: “Now that I am better informed, I feel more involved in the healing process. I feel empowered by knowledge and definitely have a more positive attitude”. 

At that moment, all my concerns vanished.

I was not causing harm!

On the contrary, by giving her more information, I encouraged her to become a protagonist in the story of her own healing. Ruth had a strong and inquisitive personality and she reinforced my belief in always guiding my practice by Hippocratic principles. I was free to move forward. 

Ruth also moved forward. Shortly after, she sent me a second email. She wanted to know how and why cancer settled in her body. She was feeling guilty for lifestyle choices she made when she was younger. She was blaming herself for being careless with her health.

At the time of cancer diagnosis, guilt is a very common feeling and I was not surprised when Ruth brought this up. We all make mistakes in life and it is common for negative feelings to resurface when one is faced with a crisis. Guilt and grief are often associated and can lead to feelings of depression and self-pity, neither of which will help someone faced with the challenges brought by a cancer diagnosis.  The physician ought to empathetically address both feelings openly and promptly encourage the patient to transition to a more productive state of mind.

With that in mind, I replied her email.

I stated that I was happy to be able to help her better understand the "internal enemy”. Unfortunately, most of the time, cancer is unpredictable. Obviously, there are known risk factors, but they do not act alone. The onset of the disease is a multifactorial random process based on one individual’s “molecular ability” to repair damaged DNA. So, there is no need for someone that had always led a healthy lifestyle to feel that they brought cancer into themselves. 

Ruth replied immediately. 

She seemed to be very grateful to be able to have a direct channel of communication with her doctor. She was not feeling guilty anymore. She realized that her lifestyle was not the sole cause of her cancer. She assumed that her diagnosis had been simply a matter of chance.

However, I was still concerned. 

Ruth was much too young for a sporadic breast cancer. She might have a genetic susceptibility and, in fact, she had told me that two of her aunts had had breast cancer. That information and the fact that Ruth had two daughters, made me consider testing her for BRCA1 and BRCA2 gene mutations. The presence of any of these suppressor gene mutations would require additional treatment and genetic counseling. 

I decided that we should meet face to face to discuss the possibility of looking for a genetic susceptibility as soon as possible.

Ruth returned to the office a few days later.

At that point, I had already reviewed all her tests and was able to reach out to all the other providers previously involved in her care. Review of the biopsy confirmed the diagnosis of an infiltrative ductal carcinoma. A test called immunohistochemistry showed that her cancer had a high proliferative index (Ki67=20%) and absence of estrogen (ER) and progesterone (PR) receptors. Additionally, a test called FISH demonstrated that her cancer cells were positive for Her-2.

The Her-2 marker is present in 20% of patients with breast cancer. The negative expression for ER and PR indicated that her disease was not hormone-related. Her-2 positive tumors have a high risk for micro-metastatic disease and relapse, making it hard to ascertain her prognosis. She would have to be treated with surgery, radiotherapy, chemotherapy and biologic-targeted therapy.

At the first consultation I had already ordered some imaging tests, including cranial magnetic resonance image (MRI) considering the fact Her-2 positive breast cancer has a higher risk for non-symptomatic brain metastases. Fortunately, all those were negative without any evidence of overt metastatic disease.

I went over the meaning of her test results, along with the prognostic and therapeutic implications. 

She came across as calm and self-confident.

She mentioned that reading the educational packet helped her better understand cancer behavior and the importance of the tests she had just completed. Her cancer was restricted to the breast. She told me that she was prepared to cope with her diagnosis and the treatment that were forthcoming. She was ready to fight to be healthy again! 

Suddenly, she started to cry. 

She stared at me and said: "Doctor, I have two daughters and I need to know if I could have passed the disease on to them.”

Ruth had always been very direct. It was good that she was asking this important question. At that particular moment, this was definitely the most important subject to be addressed and I felt that she was ready for the discussion. 

I briefly replied saying that I would refer her and her daughters for genetic counseling along with testing for the BRCA1 and BRCA2 mutations. 

Ruth then became very tense and asked me suddenly: "What happens if these evil genes turn out positive?"

I was afraid she was not yet prepared to have a detailed discussion on how we would approach her treatment if she indeed turned out to have a BRCA mutation.

I suggested first approaching the more immediate treatment decisions since it could take up to a few days to schedule the necessary genetic counseling.

I informed Ruth that the mutation test would not be a sentence in itself but rather a starting point for a shared decision-making process.

Ruth seemed to calm down and agreed with the proposed stepwise approach.

To be continued in PLOT 3 (conflict): Self-image…

*       Attention: The story 1 was published sequentially from the PLOT 1 to the PLOT 6, however it will appear backwards. So, you will always see the most recent publication. To start reading from the beginning, just browse through the numbered pages located at the bottom of the homepage. 

© Copyright 2019 Anticancerweb

 James Fleck, MD, PhD: Full Professor of Clinical Oncology at the Federal University of Rio Grande do Sul, RS, Brazil 2019

Joao A. de Andrade, MD: Professor of Medicine and Chief Medical Officer, Vanderbilt Lung Institute, Vanderbilt University Medical Center, Nashville, TN – USA 2019 (Associate Editor)