Debu Tripathy

Our country, as well as the rest of the world, is uneven in how society is treated based on many unalterable factors such as race and ethnic heritage — characteristics that permeate just about every aspect of daily life. In health care delivery, such disparities are well documented and are further complicated and magnified by associated factors such as education level, income, employment and access to care. Cancer care is among the most expensive and complicated medical deliverables and, perhaps, the most affected by racial disparities. Imbalances among racial groups that exist in many corners permeate every dimension of cancer, from lifestyle and preventive aspects to availability of cancer screening, timely diagnosis of cancer and rapid access to treatment and follow-up. Because research into this topic has increased in the past few decades, this subject has come to the forefront of government officials, the health care industry, businesses that provide and purchase health care coverage, and the public in general.

How has this information influenced policy and laws? Has it really helped level the playing field for all races and ethnicities? Are cancer outcomes starting to improve for affected racial groups?

In this issue of CURE®, you will learn more about these disparities and some of the underlying reasons we find ourselves in this situation. You will read about examples of and possible reasons for racial inequities in different parts of patients’ cancer journeys.

A deeper dive into specific ethnic and racial groups will provide some context and personalize this problem — illustrating that we all own it and need to address it as a society. As is our tradition, you will get specific facts and figures that illustrate the magnitude of the problem. For example, postoperative mortality after cancer surgery has improved over the years, but there is still a gap in death rates — it remains higher for Black patients compared with White patients, according to a large analysis using national Medicare data. Disparities in outcomes also exist for Hispanic/ Latino patients with cancer.

The past year has spotlighted racial inequities not only in the U.S., but worldwide. It has also opened our eyes as to how a major health disruption — in this case, a pandemic — can aggravate the unacceptable status quo. This issue will also provide some hopeful and positive new trends on both small and large scales that we hope can move us toward greater cancer care equality.

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The past year has spotlighted racial inequities not only in the U.S., but worldwide. It has also opened our eyes as to how a major health disruption — in this case, a pandemic — can aggravate the unacceptable status quo.

Examining Racial and Ethnic Disparities in Cancer Care

In this issue of CURE magazine, we review the current approaches for the evaluation and treatment of metastatic breast cancer, and what the future holds. In some sense, the future is now, because much of what is going on in laboratories as part of research programs is being translated into clinical trials that are currently ongoing.

The last decade has witnessed the introduction of next-generation gene sequencing and other technologies that have shown us that every cancer case is truly unique in the abnormalities that are carried in cancer cells, and that many of these alterations are “drivers” that make cancer grow and spread in an uncontrolled fashion. We have also learned that there are even differences between the cells within an individual tumor, leading to the emergence of resistance to drugs that may be initially effective.

Two major drivers in breast cancer are the estrogen and HER2 receptors, both of which can be targeted with several drugs that mostly spare normal tissue. HER2-targeted therapies, in particular the antibodies Herceptin (trastuzumab) and Perjeta (pertuzumab), have had a major impact on survival times, which have more than doubled with these drugs. It is likely that these agents not only block HER2 but also induce an immunologic response — an added benefit seen with certain antibodies. While two newer biological drugs, Afinitor (everolimus) and Ibrance (palbociclib), can significantly delay progression when added to hormonal therapy, they have not demonstrated the ability to improve survival. Triple-negative breast cancers, which lack hormone or HER2 receptors, are strictly treated with chemotherapy for the time being. However, early-stage trials with immunotherapy are showing some activity and will represent an active area for future study.

Trends in research also include more personalization based on genetic and protein markers. For example, in breast cancers that arise in the setting of inherited BRCA mutations, poly (ADP-ribose) polymerase (PARP) inhibitors can be used to interfere with DNA repair. There are also studies testing whether an expanded group of tumors that have other defects in DNA repair may also benefit.

We invite you to learn about these developments and to appreciate the need for more awareness about treatment and clinical trials. Both are needed for good care and a better future for those with advanced breast cancer.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

In this issue of CURE magazine, we review the current approaches for the evaluation and treatment of metastatic breast cancer, and what the future holds.

Metastatic Breast Cancer: The Future is Now

Patients with breast cancer are responsible for making numerous decisions about their own care, but at no time in the process are they more in the hot seat than just after diagnosis. We hope that this 

 will arm you with information that can help — but there are also many other resources available to you.

Receiving a cancer diagnosis is a turning point, a moment at which patients need to start determining what seems like the right treatment path and exerting their best efforts to make it happen.

In the whirlwind after diagnosis, emotions can be highly charged, and it’s often difficult for patients even to focus on what their doctors are saying, let alone to gather information about their disease or treatment plans. Yet patients with breast cancer need to quickly become effective partners in decision-making. How can they arm themselves with the facts and ask the questions that will lead to high-quality decisions that reflect the best evidence and their preferences, choices with which they will be satisfied long-term?

As a newly diagnosed patient, or following surgery for breast cancer, you will naturally have questions. Ask them! Ask your surgeon or medical oncologist about the stage, grade and subtype of your breast cancer and the treatments that are recommended. For each treatment, ask about the expected benefit — in terms of lowering the risks of recurrence or progression &mdash; and the anticipated short-term and long-term side effects of the complex array of possible surgical, medical and radiation treatment options. Let your care team know how you like to make decisions and whether you prefer granular statistics or a broader overview of your case to help you understand the choices. Use their expertise and experience to guide you on a course of action — but don’t be afraid to question and challenge as you need to, in order to ensure that your understanding is clear. Seek clarification over the phone or with a second visit, if needed.

Next, turn to sources besides your doctor by seeking a second opinion and/or gathering information from some reliable and well-organized websites, such as the National Cancer Institute (cancer.gov), the American Society of Clinical Oncology (cancer.net), the National Comprehensive Cancer Network (nccn.org/patients) and the American Cancer Society (cancer.org).

Your goal is to understand the underlying risk of recurrence with no therapy and the amount by which a treatment will lower it quantitatively. Even though there’s a lot of variability in outcomes, this will provide you with an estimate that you can then weigh against expected side effects, as well as personal preferences. For example, the very small possibility of long-term neuropathy from paclitaxel may not be worth a 5 percent drop in recurrence risk for someone who enjoys playing the piano. Similarly, specific issues may affect whether one might go with more conservative or aggressive surgery. In this magazine, you will review both medical facts and patients’ own perspectives — both part of the fabric of making sound choices.

Helping to shape your own treatment plan may make you feel more hopeful, not only because you’ll know that the strategy is well-suited to your needs, but because these decisions will banish some of your uncertainty about what to expect in the weeks and months ahead. Do your best to keep a clear head and recruit help from loved ones, if necessary, as you direct your attention to learning about treatments that might be right for you. It’s a worthwhile investment of time. C 

A Worthwhile Investment

Immunotherapy — in the area of cancer treatment, it’s the buzzword of the moment. It would be difficult to imagine an area of the field generating more excitement and hope than immuno-oncology is sparking right now.

There’s good reason for this enthusiasm. Logically, it makes sense that there should be ways to stimulate the body’s own immune system — which is naturally primed to fight disease &mdash; to attack and kill cancer. Realistically, the idea that we can make the human immune system more potent holds up: Immunotherapy has demonstrated effectiveness in an expanding range of cancer types, with some drugs of this kind already approved.

An area of particular excitement within the immunotherapy realm is chimeric antigen receptor (CAR) T cell therapies. This technique involves removing T cells (immune cells) from a patient’s body, engineering them in a lab to include a gene sequence that programs them to recognize cancer-specific proteins and demolish cancer cells, and then infusing them back into the patient. Inside the patient’s body, the T cells not only attack cancer cells, but multiply upon encountering them.

Although none have been approved yet by the U.S. Food and Drug Administration, CAR T cell therapies are being tested widely across the cancer spectrum. While it is thought that they might make excellent treatments for solid tumors, current clinical research is farthest along in the blood cancers. In fact, as we report in this special hematology issue of 

, some very promising trials were recently conducted in both children and adults with acute lymphocytic leukemia (ALL). The results of these trials are remarkable in that they show that CAR T cell therapy extended life in many patients for a year or two or even longer, despite the fact that their ALL was relapsed or refractory.

How much CAR T cell therapy ultimately can prolong life remains to be seen, but there is hope that it will have the kind of lasting effect that few other cancer treatments have conferred. With these engineered T cells living and multiplying in patients’ bodies, our highest hope is that they will enable lifelong immunity to the cancers they treat and provide durable and even permanent remissions.

Our search for answers to this question is really just beginning, but we look forward to sharing more news with you as the story unfolds.

Immunotherapy â€“ it's the buzzword of the moment. It would be difficult to imagine an area of the field generating more excitement and hope than immuno-oncology is sparking right now.

More Than a Buzzword, Immunotherapy Holds Great Promise

As time moves on, we are seeing continual developments in the diagnosis and treatment of prostate cancer, with several recent developments of particular interest.

Yet unanswered questions persist, and some of the most controversial concern screening for the disease. How much does screening for the level of prostate-specific antigen (PSA) in a man’s blood — which may indicate the presence of prostate cancer — help men overall, and how should we balance screening programs with our concern about the unnecessary diagnosis and treatment of slow-growing cases of the disease?

The medical and scientific communities are working to resolve these questions. Some suggest changing screening eligibility requirements or raising the PSA level — or the rate of change in levels over time &mdash; that are considered high enough to warrant testing for prostate cancer. Are there specific factors upon which to selectively screen certain individuals? Another hope is that the discovery of various biomarkers may lead to a more definitive test for prostate cancer &mdash; or better yet, help us determine more clearly which prostate cancers are indolent and which are aggressive. Until that happens, we grapple with the issue of whether PSA screening is a worthwhile alternative.

Similar questions spill over into the treatment arena when prostate cancer is caught early. If a man is told to “watch and wait,” is knowing about his disease worth the stress that knowledge can cause? For those who choose treatment for this stage of disease, are outcomes good enough to warrant the common side effects that can result, including urinary incontinence and erectile dysfunction?

In more advanced cases, when treatment is more definitively necessary, we often turn to strategies that have been with us for decades. The first radical prostatectomy, in fact, was conducted more than 100 years ago, and the importance of chemotherapy in advanced — especially high-burden – disease has persisted for half a century. Yet progress is regularly being made in these areas, and newer techniques are being added to our toolbox.

In the surgical realm, there’s a growing trend toward the less invasive: robotassisted laparoscopic prostatectomy is growing in popularity, and experimental strategies include a newer form of laparoscopy known as LESS and a urethral prostatectomy called NOTES. Radiation techniques are also evolving, with a focus on higher doses that are given in shorter courses and cause less damage to surrounding tissue. And since 2010, six new medical treatments for prostate cancer have been approved, including hormonal treatments Zytiga (abiraterone) and Xtandi (enzalutamide), immunotherapy Provenge (sipuleucel-T) and the chemotherapies Taxotere (docetaxel) and Jevtana (cabazitaxel). Just in the last year, there has been evidence that earlier use of chemotherapy may be better for certain patients than waiting until hormonal therapies are no longer effective.

While we certainly can’t answer all the questions about how best to screen, diagnose and treat prostate cancer, we have endeavored to fill this special issue of CURE with a wide array of information about state-of-the-art screening and care for all phases of the disease, as well as a look at what’s on the horizon. We hope this information will help you ask the most relevant questions and make informed decisions as you determine how to live with, and fight, prostate cancer.

Medical and scientific communities continue to weigh the value of PSA screening

Resolving a Controversy: The Value of PSA Screening

Throughout the history of medicine, there has been an intriguing interplay between pop culture and science. Two feature articles in this issue are emblematic of this dynamic. Our 

 highlights the duality of this field. On one hand, the discovery of cannabinoid receptors illustrates how exogenous natural and synthetic products can interact with our bodies and produce both wanted and unwanted biological effects. On the other hand, the push for medical marijuana was not so much driven by science, as the clinical studies to date are small and inconsistent, well below the threshold required for any drug to be approved by the FDA. Rather, the driving force was a declaration of the freedom that people have over their own bodies, especially when they are suffering from symptoms that they feel are best addressed by their own choice of medications. That is not to imply an absence of clinical benefit of the many compounds found in cannabis. There is, in fact, evidence that it can help with appetite, nausea, pain and neurological disorders such as refractory seizures. But without significant public and private funding, we will not have the high-level proof needed for mainstream adoption, despite the numerous states now legalizing its medical use.

 is another example of folklore that could actually have a scientific basis. Cancer cells do exist in an acidic environment due to their high metabolism and restricted blood supply, but is this a cause or an effect? While our pH is tightly regulated, we may be able to control it at a regional level, or tweak it enough to have a biological effect. Even though there is not enough data to alter one’s lifestyle or diet solely for this purpose, research into cellular metabolism and the tumor microenvironment is growing at a rapid pace. This line of investigation has both diagnostic and therapeutic implications, but we are only scratching the surface. It would therefore be premature to completely sideline the notion of pH control — probably not by diet alone, but with other pharmacological (or possible natural product) means in the future.

The lesson to be learned from the cultural and scientific tug of war in medicine is that the two together may hasten our arrival to the truth of many matters. Remembering the many examples of ancient herbal remedies that form the basis of modern medicines, we should adopt a combination of open-mindedness (creativity) and skepticism (scientific rigor) — two ends of the spectrum that circle together to advance medicine, and much more.

Throughout the history of medicine, there has been an intriguing interplay between pop culture and science.

A Cultural and Scientific Tug of War

View the Immunotherapy Special Issue here

For many years, scientists were able to demonstrate that the immune system was active against cancer, but there was a divide they weren’t able to cross. They couldn’t apply that theory to the treatment of cancer until they learned more about how the immune system controls itself.

Now, that door is open, and a host of new therapies are beginning to pass through it.

Because the immune system is very tightly regulated to prevent it from attacking its host, it tends not to react against a lot of the things that can go wrong within our bodies, including cancer. To create effective immunotherapies, we needed to understand this “tolerance” and figure out how to wipe it away.

Recent insights into that dynamic have resulted in a host of new immunotherapies, including the checkpoint inhibitors Opdivo (nivolumab), Keytruda (pembrolizumab) and Yervoy (ipilimumab). By interfering with the so-called “checkpoint” mechanism that keeps the immune system at bay, these medications free up T cells to attack cancer cells. Other immunotherapy types include vaccines, bispecific monoclonal antibodies and laboratory-engineered T cells that are primed to fight cancer.

Due to these recent advances, we now have approved immunotherapies for melanoma, lung cancer and acute lymphoblastic leukemia, and may soon be able to treat other cancer types, including renal and breast, as well as additional hematologic diseases.

Perhaps the greatest appeal of immunotherapy is its lasting effect. Once the immune system has been programmed to fight cancer, it maintains an active surveillance, just as it does against other infections. Theoretically, after immunotherapy treatment has stopped, a patient’s immune system should remain prepared to fight the disease, even if the illness goes away and then recurs. This would represent a major advance in treatment, since cancers often become resistant to other types of medications, including targeted therapies.

The question we will face in the immediate future is whether we can achieve that lasting effect with the strategies currently available. With that in mind, an important job for researchers will be to determine the ideal length of treatment with some of the new immunotherapies, and whether they may need to be combined with other treatments.

The government, too, will play an important role in immunotherapy development. While pharmaceutical and biotechnology companies don’t often fund basic immunology research, the U.S. government does, and that contribution has been crucial. These recent successes highlight the need for the government to remain an active player in the area of immunotherapy, and to make the long-term investments needed to effectively fight cancer.

Understanding how the immune system controls itself has led to advances in immunotherapy.

Crossing the Divide

Debu Tripathy, editor-in-chief of CURE and chair of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, discusses adding the targeted drug Ibrance to the hormonal drug Faslodex.

This trial, of women with previously treated hormone receptor-positive, HER2-negative breast cancer, was presented during the 2015 annual meeting of the American Society of Clinical Oncology, a gathering of nearly 30,000 oncology professionals taking place in Chicago.

Debu Tripathy Discusses a Clinical Trial of Ibrance in Breast Cancer

There is so much attention on the aggressiveness and dangers of cancer – and rightly so, as it is a major cause of death in our society.  However, there is a flip side to this story – a diverse group of low-risk cancers, or "precancers" that could in some cases even be better left undiagnosed, as the treatment may actually cause more harm than good. These types of malignancies include diagnoses like "in situ" or "non-invasive" cancers that are commonly seen in the breast, prostate and cervix, or "borderline ovarian tumors." In many cases, they do not have the potential to invade other tissue or to spread, so they don't carry the same risks of illness and death. Some have even advocated that we rename these diseases without using the words "carcinoma" or "cancer," which bring out fear and anxiety and also motivate patients, as well as clinicians, to carry out more aggressive treatments.  However, these low-risk cancers can sometimes co-exist with more dangerous invasive (or infiltrating) cancers, and as they are typically treated with surgical removal, there can still be recurrences over the course of time, which can be either in situ or invasive. They rarely can result in death. However, these bad outcomes are unusual enough that when one looks at large population statistics for many of the in situ types of cancer, survival rates are indistinguishable from the normal population.  So, what are medical experts and even some patient advocates now saying?  The messages are mixed as there is controversy that balances the small risks of these cancers against side effects of diagnosis and treatment.  For one, there are calls for modifying our cancer screening procedures – this is particularly true for breast and prostate cancer, where "overtreatment" of harmless cancers carry significant short- and long-term side effects. We also need to develop better imaging and tissue-based tests to identify the rare aggressive cancer hiding among a sea of low-risk cases. Finally, we need to make sure that physicians and the public are up to date on the latest recommendations and developments in this area, as it will continue to evolve.

Sorting out the low-risk cancers

editor-in-chief, is in Chicago for the annual meeting of the American Society of Clinical Oncology and is reporting on the latest in metastatic breast cancer. There are several targeted drugs that are being tested in early studies that appear promising. "A new drug, known as AMG-386 or trametinib, is being tested with taxol. At early glance seems to be a very active combination," he says. "But this is really an incomplete observation. We'll need to see how long these remissions last and how they compare to other drugs."The class of drugs called CDK4/6 inhibitors are also being looked at closely by scientists. "In hormone receptor-positive cancers, these drugs have already shown pretty big improvements in disease-free outcomes and may be on the verge of approval," he says. One drug is also being tested in triple-negative breast cancer. The usefulness of PARP inhibitors is still being explored for patients with metastatic breast cancer in women with BRCA mutations. A recent study of veliparib is now reporting results that show it may have activity in patients with BRCA 1 or 2 mutation.