Elizabeth Gardner

When treating older patients with HER2-positive or triple-negative breast cancer (TNBC), life expectancy should always be taken into consideration when deciding the goals of treatment, according to a presentation by geriatric oncologist Hyman Muss, MD,&nbsp;at the 2017 Lynn Sage Breast Cancer Symposium.

"The real question isn't how old the patient is, but what their life expectancy is," said geriatric oncologist Hyman Muss, MD, of the University of North Carolina School of Medicine, at the symposium, which was sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center. "Then you calculate the risks and benefits of toxicity, and then put it all together with the defining goals of treatment. And the goal is not always longevity."

For example, while younger patients can still function reasonably well during chemotherapy and will have time to recover from side effects, older patients may be debilitated to the point where they need to move from independent to assisted living, or even full nursing home care. Moreover, patients older than 65 have significantly greater risk of being hospitalized for side effects from chemotherapy. One study showed that for some regimens, their risk was triple that of patients younger than 65.

"This is the worst thing for an older patient," Muss said. "It can be the beginning of going to a skilled nursing facility, falling, and having numerous other problems." Staying out of the hospital may take priority over gaining the benefits of chemotherapy, which may be marginal any way if the patient's tumor is 1 cm or smaller, Muss said.

More than 40% of new breast cancer diagnoses are in women 65 and older. In the United States, the median age for a breast cancer diagnosis is 62 years and the median age of death is 68 years, Muss said. But there are also 3 million breast cancer survivors who are older than 65, according to the SEER database.

For older patients, Muss said, clinicians must ask 2 questions that they might not ask for younger ones:

What is the patient's life expectancy without cancer?

Using a life expectancy calculator from the University of California at San Francisco,

Muss walked through a comparison of 2 patients in their late 70s. The first had excellent health according to her own assessment, had no health issues besides cancer, and lived entirely independently. Her 5-year all-cause mortality risk was between 4% and 23%. The second, a former smoker, had diabetes and COPD and one hospitalization in the past year, rated her own health as fair. Her 5-year mortality risk was 69%.

a tool from the United Kingdom&rsquo;s National Health Service that helps clinicians and patients evaluate the benefits of various  treatment options following breast cancer surgery. It presents survival estimates with and without adjuvant therapies. The model takes into account all-cause mortality, and recommends adjuvant therapy only for patients with a 5% or greater chance of surviving for 10 years. If it's less than 3%, adjuvant therapy is not offered at all because the side effects exceed the potential benefit.

While healthy older patients can make treatment choices similar to younger patients, and truly frail ones may need only palliative care, there's an &ldquo;in between" group that can be treated successfully with some preparation to address their potential vulnerabilities. For example, Muss strongly recommended a cardiology consult if an older patient has risk factors for congestive heart failure. Proactive beta-blockers or ACE inhibitors may help reduce toxicity during treatment.

Muss said sentinel node biopsies might be worth the time and cost to help an older patient decide whether the benefits of chemotherapy are worth the risks and the quality of life impact, especially in cases of triple-negative breast cancers where the tumor is 1 cm or 2 cm. "If they say they are absolutely never going to consider chemo, then don't do it," he said. "But sometimes when people say they will never do chemo, it's before the fact, and when they get the results it changes their mind."

Barcenas CH, Niu J, Zhang N, et al. Risk of hospitalization according to chemotherapy regimen in early-stage breast cancer

Lee S, Smith A, Widera E, et al. ePrognosis website. https://eprognosis.ucsf.edu/. Accessed September 17, 2017.

PREDICT. Public Health England and Cambridge University website. http://www.predict.nhs.uk/. Updated May 2017. Accessed September 17, 2017.

The first patient should receive the same treatment as a younger patient if her cancer is likely to recur within 5 years, Muss said. The second one has both a higher likelihood of dying from something else before her cancer recurs, and a higher risk of being debilitated by chemotherapy, making the treatment decision much less straightforward.

Articles

Hyman Muss, MD, discusses special considerations that should be taken when treating older patients with&nbsp;HER2-positive or triple-negative breast cancer.

Life Expectancy Should be a Consideration When Treating Older Breast Cancer Patients, Expert Says

HER2-positive breast cancer has gone from "worst to first" because of the success of the monoclonal antibody drug trastuzumab (Herceptin) in combination with chemotherapy, said breast oncologist Harold Burstein, MD, of the Dana-Farber Cancer Institute, speaking Saturday in Chicago at the 19th Annual Lynn Sage Breast Cancer Symposium, sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Disease-free survival rates have increased so dramatically since trastuzumab was introduced in 1998, and without significant toxicity from the drug, that, for a large proportion of patients, being diagnosed with this aggressive cancer is not the dire event it used to be.

About 1 in 5 of the 250,000 new breast cancers diagnosed every year is HER2 positive. About half are stage I and the remainder are stage II or III. Though HER2-positive cancers are more common in young women, they can occur at any age.

"Patients with stage I disease are doing very well with simple chemotherapy and trastuzumab and need nothing further," Burstein said. Patients with more advanced disease may get additional benefits from the use of 2 more recent agents, pertuzumab (Perjeta), approved for patients with HER2-positive metastatic breast cancer in 2012 and for neoadjuvant breast cancer treatment in 2013; and neratinib (Nerlynx), approved for extended adjuvant treatment of early stage HER2-positive breast cancer in July.

Burstein noted that more research needs to be done to determine where pertuzumab and neratinib are best incorporated into treatment regimens; currently, he recommends adding pertuzumab to trastuzumab for stage II or III disease, and adding neratinib at the beginning of year 2 for ER-positive tumors. He recommends caution in using neratinib because of significant side effects. The most common is diarrhea, which was severe in almost 40% of patients.

However, trastuzumab remains the starting point. A study of more than 4000 patients, published in 2014, showed that adding trastuzumab to chemotherapy led to a 37% relative improvement in overall survival, increasing 10-year survival from 75.2% to 84%. The 10-year disease-free survival rate increased from 62.2% to 73.7%. All patient subgroups benefited.

The HERA trial found that a year of trastuzumab treatment is optimal.

A 2-year course did not improve disease-free survival and was associated with more side effects. However, the PHARE trial,

published in 2013, found that 6 months on trastuzumab was almost as beneficial and should be considered in areas of the world where adequate supplies of the drug are an issue, Burstein noted.

Studies also showed that trastuzumab is most effective when it is begun concurrent with chemotherapy rather than sequentially. Some studies suggest that chemotherapy will become less important as targeted therapies improve, Burstein said, though he doesn't anticipate being able to bypass chemotherapy altogether.

Burstein believes, based on his clinical experience, that trastuzumab works even better on HER2-positive tumors than published studies suggest, and that some of the patients studied may not actually have had HER2-positive disease.

"Our pathology has gotten much better and we can more reliably identify who really has HER2," he said, though he notes that accurate identification of HER2 is "the single most discussed" topic among Dana-Farber's tumor board. He expects that future studies with more precise pathology will bear out his clinical experience.

Burstein also suspects that trastuzumab may be somewhat overutilized because of "fear of missing out" when equivocal pathology results suggest HER2 positive disease but do not confirm it. "We have invested too little in gauging which tumors truly respond to treatment." He also called for greater investment in quality assurance in immunohistochemistry testing.

Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/abstract

Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for humanepidermal growth factor receptor 2positive breastcancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.

. www.scribd.com/doc/316400360/liposarkom. 2014;32:3744-3752.

Goldhirsch A, Gelber RD, Piccart-Gebhart M, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.

. doi.org/10.1016/S0140-6736(13)61094-6. 2013;382(9897):1021-1028.

Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomized phase 3 trial.

. www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70225-0/fulltext. 2013;14:741-748.

HER2-positive breast cancer has gone from &quot;worst to first&quot; because of the success of the monoclonal antibody drug trastuzumab in combination with chemotherapy.&nbsp;

Trastuzumab Has Radically Improved Prognosis for HER2+ Breast Cancer

Breast cancer in younger women needs a different adjuvant treatment strategy from that used in post-menopausal women, but it may not have to include suppressing ovarian function, according to Ruth O'Regan, MD, at the 2017 Lynn Sage Breast Cancer Symposium.

Patients have a hard time with artificially induced menopause and some research suggests it may have a negligible effect on the success of their treatment, said O'Regan, division chief of hematology and medical oncology at the University of Wisconsin. She spoke Friday at the symposium, which is sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

"We need to hone in on getting a biomarker for who needs ovarian suppression," she said, noting that among women under 35, 20% stop taking the associated endocrine therapy because the side effects are too onerous.  However, as long as they continue to take tamoxifen as prescribed, some studies show equivalent survival and recurrence rates.

Only about 1 in 5 new cases of breast cancer between 2009 and 2013 were in women under 50, according to SEER data, but while relapse-free survival rates are virtually identical for all age groups over 40, rates are significantly lower for women younger than 40 (Azim, Clin Ca Res 2012;18:1341-51).

There is some sentiment that breast cancer in younger women is a different disease, O'Regan said, but the difference is primarily that premenopausal women are more likely to have triple-negative breast cancer and less luminal A cancer. The overall adjuvant regimen recommendations are currently the same for both age groups, except that for the younger group, they include ways to preserve fertility and minimize side effects from longer-term use of tamoxifen or other agents.

O'Regan reviewed research for several adjuvant regimens, including tamoxifen alone, tamoxifen with ovarian function suppression (through oophorectomy, radiation, or use of LHRH agonists), and exemestane with ovarian function suppression. Results of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) showed that the regimens were similar in effectiveness among women who had not had chemotherapy, but they differed significantly in the number of side effects. Exemestane was associated with more musculoskeletal problems and osteoporosis2 side effects that O'Regan said are particularly problematic for younger women who may be on these treatment regimens much longer.

The SOFT study specifically compared tamoxifen with and without ovarian suppression. The 5-year freedom from breast cancer rate was 95.8% for those treated with tamoxifen alone versus 95.1% and 97.1% for tamoxifen or exemestane plus ovarian suppression. In the 3 groups, respectively, there were 6, 7, and 3 distant recurrences at 5 years.

While there was almost no difference in freedom from breast cancer or freedom from distant recurrence among women who not received chemotherapy, ovarian function suppression significantly increased the risk of hot flashes, sweating, insomnia, osteoporosis, and hypertension, among other symptoms. O'Regan noted that patients might be at risk of developing premature coronary artery disease as well.

However, for women who had had chemotherapy, both studies showed clear improvement in recurrence rates from including ovarian function suppression as part of the adjuvant regimen.

Those treated with tamoxifen alone had a 78.0% 5-year freedom from breast cancer rate compared with 82.5% and 85.7% for those treated with ovarian suppression and tamoxifen or exemestane, respectively. The freedom from distant recurrence rate was 83.6% for tamoxifen alone and 84.8% and 87.8% for those treated with ovarian suppression and tamoxifen or exemestane, respectively. When compared with tamoxifen alone, these were statistically significant.

"Given the added toxicities [of ovarian function suppression], we need a better way of working out which patients need this approach," O'Regan said.

Several areas still require additional research, O&rsquo;Regan pointed out. Specifically as it comes to biomarkers for selecting ovarian function suppression. Right now the progesterone receptor and the Ki-67 protein have both shown some promise as biomarkers, but more work is needed.

Breast cancer in younger women needs a different adjuvant treatment strategy from that used in post-menopausal women, but it may not have to include suppressing ovarian function.

Role of Ovarian Function Suppression Still Unclear in Breast Cancer

Figuring out how a certain genetic result found through multigene testing might change not only the type of intervention but its timing is the chief challenge, according to Mark Robson, MD.

Multigene panel testing offers the ability to identify genetic mutations in patients with greater detail; while this is beneficial for the treatment of patients with breast cancer, he says, it also comes with challenges as the results can be difficult to understand at times, with many mutations of unknown significance unearthed in the process of the testing.

, but these new ones are challenging," said Robson, clinic director of the clinical genetics service at Memorial Sloan Kettering Cancer Center (MSK), in a presentation during the 2017 Lynn Sage Breast Cancer Symposium, which was sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Robson recommended using available data to put each patient on an "age-specific spectrum of risk," adjusting the timing of interventions to match the patient's risk of disease relative to the general population. For example, if a woman in the general population should start screening mammograms at age 40, a woman carrying the

gene variant has the same level of disease risk at age 30, and should start having screenings earlier.

Robson's presentation covered 9 genes associated with moderate cancer risk (with relative risk levels between 2 and 5):

, and the Lynch genes. A review of available studies has revealed a mixed picture. For example,

overall is associated with about the same level of risk, 2.3 to 2.4, as having 1 first-degree relative with breast cancer. However, some

These are far from the only possibilities, of course. Tests are available for dozens of gene variants that may make some contribution to breast cancer risk, either alone or in combination with other genes or risk factors. Some represent a low risk of breast cancer but elevated risk for ovarian canceror vice versa. Some don't represent any increased risk until the patient hits a certain age, and then the risk may spike to moderate or high.

Robson said clinicians must answer 2 questions as they expand the use of multigene panels in their practices. First, are the results "actionable": is the association large enough and robust enough to change a treatment recommendation? And second, do they have "clinical utility": that is, if the test is used to direct care, do patients have better outcomes? It's too early to answer the second question with large-scale studies, but Robson said some consensus is beginning to build around the first for some gene variants.

It is likely that a number of patients have these moderate risk gene variants, if testing is completed. Reviews of commercial lab data on almost 80,000 breast cancer patients showed that several genes associated with breast cancer risk have a prevalence that's comparable to

, showed a prevalence of 1.28%, and the prevalence of

Robson noted that genome sequencing is still too expensive to justify a large-scale controlled study that would reliably measure prevalence in populations that don't have breast cancer, but some studies are using data from public databases like the Exome Aggregation Consortium, a broad sample of genomic data acquired for other studies, as a reasonable proxy.

"The more we do, the more complicated it gets, unfortunately," Robson said, because gene variations can have several different versions, and some mutations have a much larger effect than others.

Patients given multigene panel tests at MSK are usually referred by their physicians because of a disease diagnosis or a strong family history, though there is no standardized path and some patients self-refer, Robson said. With the increasing availability of genome sequencing and other gene assays, more patients are likely to acquire information about cancer risk genes as a result of seeking testing on their own, or being tested for something else.

Regardless of how they learn about it, what should clinicians tell a 25-year-old patient who's facing elevated risk a decade or two from now? He suggesting the following example: "We understand more about your lifetime risk, and we know that when you're 40, we need to start doing something different."

Figuring out how a certain genetic result found through multigene testing might change not only the type of intervention but its timing is the chief challenge, according to Mark Robson, MD, in a presentation at the 2017 Lynn Sage Breast Cancer Symposium.

Determining the Risk Associated With Mutations Identified From Multigene Testing

Can a computer  even IBM's Watson supercomputer with the power of 6000 high-end home computers &mdash; replace an experienced oncologist in selecting the best cancer treatment option from a complex menu of possible regimens?

No. At least not yet. But, according to Andrew Seidman, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), who is helping IBM develop an application called Watson for Oncology, Watson has potential to be a valuable partner in helping him process the deluge of new information in his field.

"We are faced with exponentially growing data from all over the world,"Seidman said during a presentation at the 19

Annual Lynn Sage Breast Cancer Symposium. "At best, I might scan some article titles at the end of a long day, but it's hard for me to stay at the cutting edge and feel I'm making optimal decisions."

Seidman said oncologists are particularly challenged to keep up with the data regarding cancer-associated genes. While genomic analysis may yield a long list of actionable cancer biomarkers for a given patient, Seidman says the list is about as useful to most oncologists as a clay tablet full of hieroglyphics when it comes to making treatment decisions. Crunching large amounts of data is where computers shine, and computer decision support will become increasingly important as genomic discoveries and new treatments proliferate.

But Watson needs to be taught how to crunch, and Seidman and his MSKCC colleagues spend a lot of time figuring out how to instill their expertise into Watson's computations. He estimates that Watson for Oncology and its team are "beyond 8

grade, but not yet in high school." For each individual case used to train Watson, Seidman estimates that a human physician needs to spend 5 to 7 minutes telling the computer everything it needs to know. While Watson may do well at aggregating research findings, it needs help understanding an individual patient's ability to tolerate a treatment.

The Watson for Oncology development team's "to-do" list is long:

Add surgery and radiation to the medical oncology care plans it has been learning so far

Incorporate new treatments and care advances

Teach Watson how to match patients to appropriate clinical trials

Create an interface for patients to interact with Watson

Improve Watson's ability to link data in the literature to treatment of individual patients

Connect Watson's treatment choices with outcomes.

Though several hospitals have already availed themselves of Watson for Oncology for treatment recommendations, Seidman acknowledges that the work needs to be validated. Two basic studies need to be done. "The first level is, does Watson lead to physicians changing their preconceived treatment recommendations?" he said.  "That kind of study is just beginning."

The second is more difficult, though more important: measuring whether Watson's recommended treatment plans lead to better patient outcomes than treatment plans left entirely to physician discretion.  "We are thinking about how you would design that kind of clinical trial," Seidman said.

While Seidman does not expect to be replaced, Watson may help him and other subspecialists share their expertise more widely than they can now. "There are only so many consultations you can give, and [having access to Watson] could democratize cancer consultations."  A Watson-based consultation would lack the give-and-take that two physicians can have over the phone or in email, but the computer can link the physician to relevant literature and do comparative tabulations of outcomes for different regimens. Developments in natural language processing may enable actual dialogue someday, Seidman says.

Andrew Seidman, MD, discusses the Watson for Oncology application and the potential for Watson to be a valuable partner for oncologists during the&nbsp;19<sup>th</sup> Annual Lynn Sage Breast Cancer Symposium.

IBM's Watson a Potentially Valuable Partner for Oncologists, But Still a Work in Progress

Treating cancer pain effectively is more difficult during an opioid addiction epidemic, but it's still possible with extra vigilance, careful management, and an emphasis on empathy, said Judith A. Paice, PhD, RN, during a presentation at the 2017 Lynn Sage Breast Cancer Symposium.

Both patients and physicians now approach opioid use with extra caution that is understandable in the current climate, but their caution may be excessive in some cases, said Paice, director of the Cancer Pain Program and a research professor of medicine at Northwestern University's Feinberg School of Medicine, as well as a past president of the American Pain Society.

More patients than ever are living with pain. As of 2012, there were 32.6 million people worldwide living with cancer and that number is expected to jump to 52.2 million by 2030, according to the International Agency for Research on Cancer.

Improvements in cancer treatment have led to millions of patients surviving for a decade or more, with a corresponding increase in the number who live with pain. Paice cited a review in the journal

estimating that 40% of cancer survivors live with some degree of pain, and 5% to 10% have severe chronic pain that limits their ability to function.

One in 5 childhood cancer survivors report pain.

Amid the hype concerning overuse of opioids, Paice is concerned that some patients still remain undertreated due to addiction fears that do not match the evidence. "After Prince died, people asked me to take them off their fentanyl patches, and I had to reassure them that Prince hadn't died from a fentanyl patch," she said. Though long-term opioid addiction often begins with the use of prescription painkillers like oxycodone, Paice cited research showing that 3 out of 4 such addicts acquired those pills illicitly rather than through a legitimate prescription.

Paice said both primary care physicians and insurance companies sometimes treat last year's CDC guidelines for opioid treatment as a mandate,

even though they may be too conservative to be applied to cancer-related pain. "Many of us protested the recommendation that patients be given no more than 50 mg of morphine and only a 3-day supply at discharge," she said. "Imagine that 80-year-old woman who lives far from the hospital, relies on family members, is discharged on a Thursday, and now on a Saturday or Sunday has to get a new prescription."

Paice also cited statistics showing that while there is a rough correlation between sales of prescription opioids and deaths from opioid overdose, the number of deaths specifically from prescription opioids has plateaued (though deaths from illicit opioids are still climbing).

Nonetheless, the addiction danger is real and there are possible long-term health complications from sustained opioid use, even when the patient is not an addict, Paice said. "We didn't see these effects when I was starting out in practice because we only prescribed opioids at the end of life." They include constipation, mental clouding, upper gastrointestinal symptoms, various endocrinopathies, sleep apnea, and a poorly understood risk of opioid-induced hyperalgesia. There is even some evidence suggesting that prolonged opioid use hinders healing and may increase risk of cancer recurrence.

Paice recommended the following measures when giving cancer patients the full benefit of opioid pain relief in order to minimize risks:

Assess the patient's potential for addiction. Do they smoke, drink, use other drugs, or gamble? Have they done so in the past? Do any of their biologically close relatives demonstrate addictive behavior? Have they been sexually abused (a strong risk factor for addiction)? Do they worry about becoming addicted?

Do a urine tox screen at least annually for each patient on opioids, and more frequently for those at a higher risk of addiction, to assess whether they are overusing their pain medication or abusing other substances. Use your state's prescription drug management program, available in all states, except Missouri, to check whether your patients are getting multiple opioid prescriptions filled at the same time. (Paice discovered 1 patient was getting hydrocodone from both her and an orthopedic surgeon, from 2 different pharmacies.)

It's important to make sure patients are using their opioids for pain, rather than to relieve anxiety or help them sleep. "It's acceptable to take your medication before bed if you have vertebral fractures," and know that you'll have pain when you lie down, Paice said. "But if you're taking it every night at 9 to make you sleepy, we have a problem."

Illicit users of prescription opioids get their drugs from legitimate users, so patients need to be on guard. If patients come up short on their pills, they may be taking too manyor maybe someone is stealing them, Paice said.  "I tell patients, 'Maybe it's not your grandkids, but it's their friends.'" Patients who have pills they no longer need should dispose of them through a formal drug take-back program.

All cancers (excluding non-melanoma skin cancer) estimated incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer website.

http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx

Heathcote LC, Eccleston C. Pain and cancer survival: a cognitive-affective model of symptom appraisal and the uncertain threat of disease recurrence.

2017;158(7):1187-1191. doi: 10.1097/j.pain. 0000000000000872.

Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain  United States, 2016.

2016;315(15):1624-1645. doi: 10.1001/jama.2016.1464.

Judith A. Paice, PhD, RN, discusses the best way to approach pain management in breast cancer.