Breast Cancer Survivorship: Can We Get It Right?

The care of more than 3 million breast cancer survivors in the United States consumes about one third of overall breast cancer expenditures, reported Michelle E. Melisko, MD^[1] (University of California, San Francisco) in a stimulating education session at the 2016 San Antonio Breast Cancer Symposium (SABCS).

From an economic perspective alone, this is a wake-up call for all stakeholders. The breast cancer community is now engaged in a search for models for delivery of cancer-related services for patients who have completed active therapy. The diversity of care required by cancer survivors poses significant challenges to devising universal guidelines.

The Quandary Over Survivorship Care Plans

The optimal model and strategy remain unclear, said Dr Melisko, but must involve four main domains: prevention, surveillance, intervention, and coordination. Current models favored in the United States are those in which the care of cancer survivors is shared between the oncologist and primary care clinician or between the oncologist and physician extenders (nurse practitioners and physician assistants), consultative clinics, physician extender-led survivorship clinics, and multidisciplinary survivorship clinics.

Dr Melisko's message was clear: We need better tools to stratify patients on the basis of relapse risk. Accurate risk assessment allows for the design of optimal care plans and best use of resources. A key component of care, reported Dr Melisko, is the provision of psychological support. Dr Melisko cautioned participants against ordering tests that do not conform to current guidelines of the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network and called for novel research to explore the natural history of breast cancer given recent therapeutic advances. She then challenged our notion that identifying metastases early has no impact on long-term outcomes and referred to a recent opinion article published in the Journal of Oncology Practice by George Sledge.^[2] In that piece, Dr Sledge reflects on the fact that there may be important exceptions to the rule that metastatic disease is incurable and urges us to think of novel strategies to study this issue given the recent expansion of therapeutic options and our more nuanced understanding of the biological heterogeneity of metastatic breast cancer.

Survivorship care planning remains challenging and extends beyond the provision of a treatment summary and care plan. Bradley D. McDowell, PhD^[3] (University of Iowa Hospitals and Clinics, Iowa City, Iowa) presented a study in which more than 1000 women in the Midwest who were treated for stage 0-3 breast cancer were asked to report whether they had received two essential elements of survivor care planning: a written treatment summary and written instructions for routine cancer check-ups. The study found that 79% received one or both documents and that those who received both reported receiving better care than those who received neither. Of note, survivors were far more likely to receive both elements if they had a single health professional coordinating their cancer care of whom they could ask questions, suggesting that counseling and guidance are significant components of survivorship care plans.

The important issue of assessing patients' reports of the positive and negative aspects of the cancer experience and the transition from cancer treatment to "normal" life will be explored in more detail at the Cancer Survivorship Symposium being held in San Diego, California, January 27-28, 2017.

Targeting Treatment Toxicities

A focus of many of the survivorship presentations at SABCS was how best to handle the common toxicities of cancer treatments, such as chemotherapy-induced peripheral neuropathy (CIPN) and lymphedema.

Weidong Lu, PhD, MPH^[4] (Dana-Farber Cancer Institute, Boston, Massachusetts) presented preliminary results of a pilot randomized controlled trial of acupuncture for the treatment of CIPN. In this study, 20 patients were randomly assigned to receive an 8-week intervention or usual care. The investigators found that acupuncture produced a significant reduction in severity of neuropathy symptoms resulting in clinical benefit and concluded that acupuncture may be an effective treatment.

Prof Nigel Bundred, MD^[5] (University Hospital of South Manchester NHS Foundation Trust, Wythenshawe, Manchester, United Kingdom) presented results of a study from nine UK centers designed to determine the optimal method of detection for lymphedema. They compared bioimpedance to perometer readings in over 1000 patients and concluded that perometer readings were better and that more than 10% change was associated with symptoms and worsening of quality of life. The investigators found that predictors of lymphedema were best assessed 6 months after entry into the study instead of at baseline. The latter finding suggests that in clinical practice, the delaying of perometer readings may not only improve the accuracy of lymphedema prediction but eliminates the generation of useless data and expense. Body mass index (BMI), age, node positivity, and having received radiation were predictors of subsequent lymphedema risk.

The UK presentation was followed by a presentation of a study on perometer readings by investigators at the Massachusetts General Hospital.^[6] This group, led by Alphonse Taghian, MD, PhD, has previously published results on perometer-based arm measurements and recently called into question some of the "myths" regarding contributing factors to lymphedema that have long guided clinical practice.^[7]

In the study presented at SABCS, Dr Taghian and colleagues looked at the association between repeated skin punctures and subsequent risk for lymphedema. In over 600 patients, investigators compared those patients undergoing chemotherapy with central lines for access with those receiving multiple peripheral venipunctures. The study found no association between venipunctures and lymphedema. This is important because it challenges practices based solely on anecdotal evidence.

The Workup on Working Out

In an educational session, Melinda L. Irwin, PhD^[8] (Yale Center for Clinical Investigation, New Haven, Connecticut) led the call for increasing physical activity of breast cancer survivors. Caloric intake, balanced nutrition, and the impact of physical activity remain important areas of research. We will learn more about the role of adiposity, muscle mass, and bone health as current research matures, and this will inform the advice we give our patients.

Prof Elia Biganzoli, MD^[9] (University of Milan, Milan, Italy), on behalf of a team of European investigators, presented a study that explored the association between BMI and the risk for distant recurrence. Their group postulated that adiposity could influence recurrence dynamics. They studied 777 node-positive patients enrolled in clinical trials with long follow-up and found that 29% were overweight. Factors associated with higher BMI were older age and having estrogen receptor-positive tumors. It will be interesting to follow their research in order to have a clearer understanding of the interplay between metabolic parameters and tumor biology and how this could affect long-term outcomes.

Sound Advice on Adjuvant Hormone Therapy

Several large clinical trials addressed the crucial issue of extended endocrine therapy with aromatase inhibition. Data from the MA.17R study^[10] were presented last June at ASCO 2016, and additional studies from both the United States and Europe were presented at this meeting.^[11,12,13] In a very clear and insightful summary discussion, Prof Michael Gnant, MD^[14] (Medical University of Vienna, Vienna, Austria) framed the question in biological terms and gave sound advice to a confused community of patients and clinicians. He reminded the audience that half of the patients with endocrine-sensitive disease who will relapse do so after 5 years, and we could think of this as a chronic disease. Because the risk for relapse persists, it makes sense to extend adjuvant therapy. However, late recurrences may reflect less effective prior therapies.

To summarize the state of the field: We know that aromatase inhibitors (AIs) are better than tamoxifen for postmenopausal women and that prolonging tamoxifen is beneficial; for younger women, the possibility of taking tamoxifen alone—without ovarian suppression—is an important option.

Prof Gnant summarized data (some of which are unpublished) from ABCSG16, NSABP B-42,^[11] DATA,^[12] IDEAL,^[13] and SOLE, concluding that the last two studies showed no benefit for extending AI therapy for those who received prior sequential therapy starting with tamoxifen. The benefit observed in the DATA study seemed to track to those who exhibited very strong estrogen-receptor positivity. He commented that all of these trials have failed to show a strong signal supporting the use of extended AI therapy, leaving us to determine the advisability of adjuvant endocrine therapy case by case on the basis of relapse risk, patient preference, and tolerance of the drugs.

With extended AI therapy, Prof Gnant remarked, there is a steady decline in treatment adherence to actually taking the medication after 5 years in patients on clinical trials, making it even more remarkable that the studies showed an important effect from the medication when it was not used as intended. In clinical trials, there is a positive selection for patients who tolerate these drugs well, but it is important to weigh possible benefits with the risk for serious complications of treatment, such as fractures. Prof Gnant advocated using denosumab, shown to reduce the risk for fractures by 50%.^[15] He ended his presentation by stating that he doesn't think the addition of newer drugs, such as cyclin-dependent kinase (CDK)4/6 inhibitors or mammalian target of rapamycin (mTOR) inhibitors, will have significant impact on reducing late relapses and that the decision to extend AI therapy needs to be individualized.

He offered the following very sound advice: For women who were previously on tamoxifen, the addition of an AI for 2.5 to 5 years is recommended. For those who completed a 5-year course, the decision to continue needs to be individualized with consideration of her relapse risk as informed by initial tumor size, number of positive nodes, genomic profiling (favored Prediction Analysis of Microarray 50), bone health, and general health. It now appears that the greatest proportional benefit is derived by those women with the most luminal forms of breast cancer.

Radiation Compromises Implant Reconstruction

Providing personalized recommendations and supporting a patient's autonomy in decision-making are important aspects of care. Eric Winer, MD^[16] (Dana-Farber Cancer Institute, Boson, Massachusetts) touched on this briefly during his McGuire lecture, saying that that we need to help patients cope by recognizing that people are far more than their illness. He also warned that we need to "carefully consider toxicities when we are dealing with small benefits."

This later statement was exactly what led Reshma Jagsi, MD (University of Michigan, Ann Arbor, Michigan) and colleagues to design a prospective multicenter study^[17] of more than 500 patients to examine the effect of radiation on complications after mastectomy. Dr Jagsi stated that practices vary widely, reflecting historical traditions and institutional cultures. Her study, which is the largest prospective multicenter study of outcomes, examined patient-reported outcomes of complications and treatment failure. The median age of patients was 49 years, about half of the patients had bilateral reconstruction, and immediate reconstruction was less common among irradiated patients. By 2 years, they found at least one complication in a third of irradiated patients and 23% of nonirradiated patients. Bilateral treatment and higher BMI were associated with more complications. Radiation was associated with 2.64 times higher odds of complications at 2 years in patients receiving implant reconstruction. Reconstructive failure was 11.4% vs 3.4% in irradiated vs nonirradiated patients, more so for those receiving implants. The investigators concluded that radiation compromises outcomes of implant reconstruction.