Matching Therapies With Each Unique Patient, Not Just Her Disease
From Turning Point 2019
By Robert Levy
A rose is a rose, but cancer is a chameleon, often differing from one patient to the next, even in patients with cancer of the same organ or tissue.
At Dana-Farber's Susan F. Smith Center for Women's Cancers, doctors tailor treatments to the specific characteristics of each cancer and each patient. In addition to the traditional questions about a tumor's type, size, aggressiveness, and degree of metastasis, physicians are likely to focus on factors fundamental to the cancer's survival and growth. These include the bad actors within a tumor's genome, the proteins and immune system signalers on its surface, and its vulnerability to specific drug agents.
"Personalizing treatment makes it possible to match the strengths of a particular therapy to the weaknesses of a specific tumor," says Ursula Matulonis, MD, chief of Gynecologic Oncology at Dana-Farber and Brock-Wilson Family Chair. "Years of research and clinical experience have taught us which therapies, in which combinations, work best in particular groups of patients with particular cancers, and we have much to learn as well. Our goal is to find customized treatments that put our knowledge to work for all of our patients." This approach can in some cases improve quality of life by ensuring that patients don't receive more treatment than necessary, or treatments that are unlikely to be effective.
Susan F. Smith Center physicians also are customizing treatment in ways that go beyond strictly medical considerations and address patients' personal values and priorities. A woman's family or career goals, her concerns about the long-term side effects of certain treatments, her stage of life – all may be considered in the treatment approach she and her physician choose.
An Abundance of Considerations
In breast cancer, a wide range of factors come into play when crafting a treatment plan, says Sara Tolaney, MD, MPH, director of the breast oncology clinical trials program and associate director of the Susan F. Smith Center. The first is whether the disease is metastatic or confined to the breast. Tumor samples are then analyzed to determine whether the cancer cells carry receptors for the hormones estrogen and progesterone, and whether they test positive for the HER2 protein.
"At initial diagnosis, we determine which of these three subtypes of breast cancer the patient has: hormone receptor-positive, HER2-positive, or triple-negative," Dr. Tolaney says. "We also assess whether the patient has other health conditions that influence the optimal treatment regimen."
Personalizing therapy involves making finer and finer distinctions within each subtype of cancer. Often, that involves molecular tests to determine whether the tumor cells harbor specific genetic abnormalities or carry certain telltale proteins on their surface. Many patients with metastatic breast cancer, for example, have their tumor tissue molecularly tested in Dana-Farber and Brigham and Women's Hospital's Profile program for genetic irregularities.
For breast tumors that have not metastasized, physicians follow a similar process of zeroing in on the appropriate treatment. In some cases, this involves examining how well a tumor responded to a previous therapy. This is particularly clear in the case of "neoadjuvant" treatment, in which patients receive drug therapy to shrink their tumor prior to surgical removal.
"In patients with stage 2 or 3 HER2-positive tumors, recent data show that patients who received Herceptin [a drug targeting such tumors] plus chemotherapy before surgery, but still had breast cancer cells in the tissue removed at the time of surgery, did much better if they then switched to the drug T-DM1, compared to those who just continued Herceptin," relates Nancy Lin, MD, associate chief of the Division of Breast Oncology at the Susan F. Smith Center. T-DM1 consists of a chemotherapy agent tethered to Herceptin: the Herceptin acts like a courier delivering the chemotherapy directly to the tumor. "We learned that we can improve outcomes by tailoring treatment based on response to pre-operative therapy."
For all the impact that molecular research is having on cancer treatment, physicians also take a variety of more familiar, "macro" factors into account. Among these is a patient's age. Susan F. Smith Center physician-researcher Rachel Freedman, MD, MPH, for instance, is leading several clinical trials exploring whether reduced-toxicity therapies can still produce good results for older patients with breast cancer while decreasing side effects.
Ann Partridge, MD, MPH, founder and director of the Susan F. Smith Center's Program for Young Women with Breast Cancer, describes how other, more personal considerations can factor into treatment. "For younger women who desire to have children after their breast cancer therapy, we offer referral to our fertility specialists to see if embryo or egg preservation should be considered prior to chemotherapy. There are also some chemotherapy regimens that we can choose to use for patients that may have less impact on fertility and medicines that can be given concurrently with chemotherapy to try to preserve fertility."
Is Less More?
Personalized treatment often involves more narrowly targeted therapies, but it need not mean more therapy in total. A focus of recent research by Eric Winer, MD, in fact, is whether "less can be more" in the treatment of some breast cancers.
Dr. Winer, chief of the Division of Breast Oncology at Dana-Farber, is quick to point out that a "less is more" approach is suitable only for specific subsets of patients. He cites two areas where the approach has worked "phenomenally well."
The first involves women with breast cancer that is hormone receptor-positive and HER2-negative, which has a relatively low risk of recurring, and is highly sensitive to hormone-blocking drugs. Standard treatment calls for hormonal therapy in combination with a substantial course of chemotherapy, but "over the past five years we've learned that these patients can still do very well if we pull back on the amount of chemotherapy," Dr. Winer remarks. The second example involves women with early-stage, HER2-positive breast cancer, who are commonly treated with chemotherapy and the HER2-targeting drug Herceptin. Here, too, clinical trials have shown that patients can be safely and effectively treated with very limited amounts of chemotherapy.
Both examples stem from a desire to ease the sometimes painful and draining side effects of chemotherapy without reducing the effectiveness of treatment. "All of our therapies have the potential to cause side effects, which can in some cases have profound consequences for patients," comments Joyce Liu, MD, MPH, director of gynecologic oncology clinical research at the Susan F. Smith Center. "Even in situations where 90% of patients tolerate a treatment well, 10% are still having complications. If we can use our understanding of the differences between tumors to cut down the use of unneeded treatment and reduce that suffering – in a way that's safe – we need to try."
Customizing Gynecologic Treatments
The treatment of gynecologic cancers is personalized in many of the same ways as breast cancer treatment – with a focus on cancer type, genomics, and the patient's age, health, and life goals.
Panos Konstantinopoulos, MD, PhD, director of translational research in Gynecologic Oncology, illustrates how cancer subtype influences treatment in ovarian cancer. "The most common histological subtype is high-grade serous ovarian cancer, but there are others, like clear cell, low-grade serous, low-grade endometrioid, and mucinous ovarian cancers," he explains. "They all have their own molecular underpinnings, and we treat patients differently. For some subtypes, like low-grade serous, for example, we use hormonal therapy more frequently. Other subtypes, like mucinous ovarian cancers, are treated more like gastrointestinal tumors."
And, as in breast cancers, treatment is often tuned to tumors' genomic susceptibilities. Ovarian cancers hampered from repairing their DNA are often treated with PARP inhibitors or ATR/Chk1 inhibitors, which put the brakes on cancer cell division. In endometrial cancer, as in breast cancer, physicians want to know if the cells sport hormone receptors on their surface and if they have a DNA-repair deficiency. So, too, in cervical cancer, where the presence of PD-L1 on the tumor cell surface prompts treatment with the drug pembrolizumab.
"Genetic research has allowed us to understand that each tumor is different and to look for the genetic alterations that are driving tumors," Dr. Konstantinopoulos remarks. "This work, in combination with clinical research, has helped us understand why certain drug agents work well for some cancers and not others, why some patients develop resistance to certain drugs and others don't, and how to find novel drugs for these patients. As this work advances, so will the use of personalized therapy."
Here are some examples of how the treatment decision-making process works for metastatic breast cancer:
- Triple-negative tumors are tested for the presence of PD-L1, a protein that protects the cancer from an immune system attack. Patients whose tumors test positive for PD-L1 may be treated with chemotherapy and an immunotherapy drug that blocks PD-L1 and exposes the tumor to an immune system assault.
- Patients are also recommended to undergo genetic testing to see if they have a BRCA gene mutation. If the test comes back positive, patients are often treated with drugs known as PARP inhibitors, which undermine cancer cells' ability to keep their DNA intact.
- Patients whose tumors are found to carry the estrogen receptor are treated with drugs known as CDK4/6 inhibitors, which work by stalling the process of cell division. If the tumor has a mutation in the PI3K gene and stops responding to a CDK4/6 inhibitor, research suggests it can be controlled by a combination of hormonal therapy and a drug called alpelisib, which blocks PI3K. Alpelisib was recently approved by the Food and Drug Administration, but there are many questions about how it should be used in clinical practice, particularly because it has a number of side effects.
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