The unmet needs of older patients with breast cancer

Older patients are under-represented in breast cancer clinical trials and, although drug regulators discourage studies with upper age limits, exclusion criteria still mean that patients over 65 years old are frequently left out of important research. Without clinical trial evidence of efficacy and safety in older people, clinicians may be reluctant to prescribe novel agents, especially to their frailer patients, and getting reimbursement for drug doses, schedules and combinations adapted for older patients can be challenging. How are leading breast cancer researchers addressing the need to include more of the growing population of older patients in clinical trials? Medical journalist, Jenny Bryan, reports.

Nearly 50% of patients with cancer are aged 65 years and over, as are 55% of those with breast cancer1 but older patients are poorly represented in clinical trials. Eligibility criteria, concerns about toxicity and patient age, and the burden of trial participation have been identified as the main barriers.2

Older patients who are included in breast and other cancer trials are generally fitter than expected for their chronological age, with fewer comorbidities, and study results may not be indicative of outcomes in frailer, older patients eligible for newly approved therapies.

“Patients in trials tend to be younger and fitter or, if they are older, they have minimal heart, kidney or other end organ damage,” explains Etienne Brain, Institut Curie - H?pital René Huguenin, SaintCloud, France, and past Chair of the EORTC Breast Cancer Group. “This creates a gap between the trial population and the patients we see in clinical practice. When a drug is approved, the label may say that it works irrespective of age, but that only means for the type of older patient in the clinical trials.”

Laura Biganzoli, Hospital of Prato, ASL Toscano Centro, Prato, Italy, points out that a lack of older patients in clinical trials can lead to delays in prescribing new agents to fit older patients, and frailer patients may miss out altogether.?

“Everybody recognises that this is an important issue, and we need to encourage pharmaceutical and other sponsors to support trials in older patients. These studies may require innovative designs and different endpoints from standard trials, but accrual of older patients can be really fast at centres where geriatric clinics are held alongside cancer clinics and there is a culture of oncogeriatrics,” she says.

Hans Wildiers, University Hospital Leuven, Belgium, past President of the International Society of Geriatric Oncology (SIOG) and past Chairman of the Cancer in the Elderly task force of the EORTC, suggests that some trial sponsors are concerned that if less fit, older patients are included in clinical trials, they will be more likely to experience toxicity, leading to poorer overall results.

“There is also the problem that very few frailer, older patients are likely to tolerate the side effects of standard chemotherapy, which is the comparator in many studies of new agents, and there is a reluctance to reduce the doses of any of the drugs in clinical trials to adapt to the needs of older patients,” he says.?When new agents are introduced for breast cancer, oncologists may give them to their frailer, older patients at lower than recommended doses to reduce toxicity, with different and empirical schedules including combinations with less harsh forms of chemotherapy. But, as Brain points out, this is rarely based on clinical evidence from registration trials and may lead to reimbursement or administrative issues.

“For metastatic HER2+ disease in older patients, SIOG guidelines support use of metronomic cyclophosphamide instead of taxanes to be given with trastuzumab and pertuzumab but, without registration trials, it can be a problem to get reimbursement,” he says.

Leading research and professional organisations such as BIG, EORTC and SIOG are collaborating to raise awareness about the needs of older patients with breast cancer and to press for their inclusion in clinical studies, including registration trials.

The US Food and Drug Administration (FDA) has consistently encouraged enrolment of older people in drug registration trials and has recommended grouping older adults into narrower age groups for data analysis, such as 65 to 74 years old, or 75 to 84 years old, instead of a broad group of patients over 65 years.3 Similar efforts have been made by the European Medicines Agency (EMA).4 However, progress is slow.

“The only solution is for the FDA and EMA to make it mandatory for there to be a sub-group analysis in older patients in registration trials for new cancer medicines. T his needs to include people in their 80s, not just those who are 66 or 67 who are less likely to be frail,” says Wildiers.

Biganzoli agrees. “We also need to include primary endpoints focused on patient function that are relevant to older people, together with geriatric tools and scales.” she says.

As well as including more older patients in trials, and reducing exclusion criteria, Brain favours more opportunities in major studies for using lower drug doses in older patients, with stepwise dose escalation strategies.

“I understand that registration of a new medicine needs to be achieved as rapidly as possible but, as soon as it is approved, there should be a commitment to carry out dosing studies in older patients,” he says.

Like Biganzoli, he would also like to see different endpoints in breast cancer clinical trials for older patients that reflect the priorities of older compared to younger patients.

“The balance between extra time and quality of life is different, so a woman with breast cancer in her 30s will want to live long enough to bring up her children, while the majority of older patients want to live well with their cancer for their remaining life. We therefore need quality of life rather than progression- or disease-free survival as the primary endpoint in trials with older patients, and the regulatory agencies are looking carefully at this,” says Brain.

He believes that ‘hidden ageism’ needs to be addressed in clinical trial recruitment, as there may be an assumption that older people will not understand the purpose of a trial or the inconvenience of taking part.

“It may take more time to explain and to listen to older patients, but we need to take that time as part of being a clinician. We are used to being in a rush to use the latest technology, make the diagnosis and get people on treatment, but it’s just as important to know when to take time to explain things to our older patients. When they understand that we need to answer an important question in a trial, they can be just as likely to want to participate as younger patients,” Brain concludes.

The importance of geriatric assessment

Inclusion of geriatric assessment (GA) in clinical trials to determine physiological age is widely recommended to differentiate older patients who are likely to tolerate treatment from those who are not.5 In their most recent guidance on the management of older patients with breast cancer, the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG) recommended that a screening tool should be considered as the gateway or minimum starting point to any treatment decision-making in older patients with cancer.6 SIOG also carries out extensive educational and awareness initiatives about the importance of GA and collaborates with BIG and other organisations at national and global level to advocate for greater inclusion of older patients in clinical trials.

“In an ideal world, we would do a comprehensive geriatric assessment (CGA) for all older patients with breast cancer before making a treatment decision but this is time consuming. However, we now have geriatric screening tools that accurately predict the results of a CGA, and identify patients who need a full CGA, and these can often be done in minutes,” says Nicolò Battisti, Royal Marsden Hospital, London, UK, and SIOG President-Elect.

A key tool to identify older patients warranting an oncogeriatric approach is the?Geriatric8 (G8) screening tool, which was developed to identify older cancer patients who would benefit from CGA, and is popular in clinical trials. In order to predict treatment benefits in this population, the PORTRET tool, developed in the Netherlands, has been designed to predict recurrence, overall survival and other-cause mortality in older patients with breast cancer.7 Similarly, the online Age Gap decision tool, developed in the UK, is designed to guide choices about surgery versus endocrine therapy as primary treatment in older patients with breast cancer, and in relation to chemotherapy after surgery. In order to predict the risk of severe side effects, the Cancer Aging Research Group (CARG) score has been externally validated for predicting chemotherapy toxicity in older adults with cancer, and CARG-BC has been developed to predict severe chemotherapy toxicity in older patients with early stage breast cancer.8 The CRASH score stratifies patients into four risk categories of severe toxicity.

A number of studies have now demonstrated the value of incorporating GA in cancer clinical trials for optimising care and health outcomes in older patients, including reducing treatment toxicity and discontinuation.9-11

“If we combine tools that can predict need for CGA, life expectancy, efficacy of treatment and side effects, this enriches the discussion with older patients both in clinical trials and clinical practice,” says Battisti. “These tools are now being used in good quality clinical trials in geriatric oncology. We are also making progress in convincing pharmaceutical sponsors about the importance of geriatric assessment methods in order to include more older patients in clinical trials of breast cancer.”

He believes it is a lost opportunity if older patients are missed out of clinical trials because GA tools are not included in study design.

“In some types of breast cancer, over 50% of our patients are older, and if these are excluded from clinical trials of new medicines because there is no GA, many frailer patients will miss out on new treatments when they reach the clinic,” warns Battisti.

What research is being done in older patients?

Although older patients are still infrequently enrolled in many breast cancer trials, some recent and ongoing studies have focused on the needs of older patients. In a Phase 2 study coordinated by Wildiers of pertuzumab and trastuzumab with or without metronomic chemotherapy in older patients (EORTC 75111-10114), 70% of patients had a potential frailty profile demonstrated by their G8 score.12 Results suggested that adding metronomic cyclophosphamide increased progression-free survival and might delay or supersede the need for taxane chemotherapy in this population.

In the Phase 2 EFFECT trial coordinated by Biganzoli?in women with advanced breast cancer aged ≥ 65 years, survival outcomes were comparable for nab-paclitaxel 100 mg/m2 and 125 mg/m2, but the lower dose was better tolerated with significantly less neurotoxicity.13

The Phase 3 ASTER 70s study investigated the benefits of adjuvant chemotherapy and endocrine therapy compared to endocrine therapy alone in patients with high grade oestrogen receptor (ER)positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer aged 70 years and over.14 In the primary intention-to-treat analysis, there was no statistically significant difference in overall survival between the two groups – suggesting that chemotherapy may not be needed in these older patients. There was a 20% non-adherence to treatment in the chemotherapy arm, which, it has been suggested, contributed to the failure to see a survival difference between the two treatment options. However, as Brain points out, the nonadherence rate in ASTER 70s was very similar to that seen in other major trials, including TAILORx, in younger patients.

The Phase 2 APPALACHES trial, being carried out through the EORTC and BIG network of investigators, is the first study to compare palbociclib with chemotherapy in patients with high risk ERpositive breast cancer treated with standard adjuvant endocrine therapy. About 340 of a planned 366 patients (women and men) with stage II or stage III, ER-positive, HER2-negative, early invasive breast cancer aged 70 years and over had been randomised by August 2022.

As Wildiers explains, the APPALACHES population is at high risk of relapse after surgery and, if they were younger, would probably have preventive chemotherapy with their hormone treatment to reduce their risk of metastases. However, in clinical practice, some older patients decide against chemotherapy due to its side effects and associated reduction in quality of life.

“Palbociclib has different anti-cancer effects to chemotherapy and is much better tolerated, and there is evidence that it may be as effective as chemotherapy. In APPALACHES, we are therefore looking to see if palbociclib can reduce the risk of metastases and avoid the need for chemotherapy in older patients with hormone sensitive breast cancer,” says Wildiers who is principal investigator for APPALACHES.

The primary endpoint of the study is the 3-year disease recurrence-free interval (D-RFI) rate in the experimental arm. Secondary endpoints are breast cancer specific survival, overall survival, and incidence of permanent treatment discontinuation – all at five years.

Wildiers explains that, in common with a growing number of breast cancer trials, a threshold has been set for assessing the primary endpoint, so that fewer patients are needed than for showing a statistically significant difference for an outcome that may be very similar for palbociclib and chemotherapy. For APPALACHES, this bar has been set at 92% of patients treated with palbociclib achieving distant disease-free survival at three years.

“My goal is also to evaluate outcomes at eight to 10 years, so we can see how fast these cancers are growing in older patients. Did they die of breast cancer, or were we able to prevent that so they died of something else? Alternatively, if a lot of people do develop metastatic disease, then perhaps it is not a good choice to omit chemotherapy,” says Wildiers.

For Biganzoli, the feasibility of using novel cancer treatments in older patients is also important. With this in mind, the FACILE trial is investigating the feasibility of using another CDK 4/6 inhibitor, ribociclib, in patients with advanced breast cancer aged ≥70 years. The primary endpoint is the proportion of patients who have not experienced disease progression six months after first drug administration and are still on treatment with ribociclib.

“All patients in FACILE will undergo a full geriatric assessment, and we hope that this will enable us to evaluate the feasibility of treatment related to the true health status of individual patients,” says Biganzoli.

Geriatric assessment is also a feature of the Phase 2 TOUCH trial, which is comparing neoadjuvant palbociclib, hormonal therapy and HER2 blockade, with paclitaxel and HER2 blockade in postmenopausal patients with HR positive/HER2 positive early breast cancer.

“Women over 65 years of age are receiving geriatric assessment to enable us to better understand the treatment effects in the older patients in the trial,” explains Biganzoli.

Experience in Japan

At 87 years, Japanese women have the highest life expectancy in the world, and breast cancer is the most common form of the disease in this population. In 2017, approximately 28% of the 94,612 patients diagnosed with breast cancer were over 70 years of age, 41.6% over 65 years.

Masataka Sawaki, Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, explains that data from the Japanese Breast Cancer Registry (JBCR) show that older patients (> 75 years) have more advanced disease at diagnosis, are more likely to have mastectomy, and are less likely to have radiotherapy or primary systemic chemotherapy after breast cancer surgery than younger patients.15 If they have chemotherapy, older patients are more likely to have cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or oral 5FU than standard anthracycline and taxane chemotherapy. In a survey amongst institutions in the Japanese Oncology Group, 34% of respondents said that an upper age of 80 years was an important factor when choosing surgery, and 20% put the upper age at 70 years.16 Seventy five years was generally considered to be the upper age for giving chemotherapy and 80 years the upper age for giving radiation.

“Despite the differences in stage at diagnosis and treatment, the Registry data showed similar breast cancer specific survival rates for all age groups, though the rate of other causes of death was higher in the older age group,” says Sawaki.

To better understand the need for chemotherapy in patients with breast cancer in Japan, the RESPECT trial was set up to investigate the efficacy and tolerability of adjuvant trastuzumab with or without chemotherapy in 275 patients aged 7080 years with surgically treated, HER2-positive early breast cancer.17 Three-year disease-free survival (DFS) was 89.5% with trastuzumab monotherapy compared to 93.8% with trastuzumab+chemotherapy (hazard ratio [HR] 1.36; 95% confidence interval [CI] 0.72 to 2.58; p=0.51). Common adverse events (AEs) were less frequent with trastuzumab monotherapy than with trastuzumab+chemotherapy: anorexia (7.4% vs 44.3%; p<0.0001), alopecia (2.2% vs 71.7%; p<0.0001), and grade 3/4 non-haematologic AEs (11.9% vs 29.8%; p=0.0003) respectively. Clinically meaningful deterioration in health-related quality of life was significantly less with trastuzumab alone than with trastuzumab+chemotherapy at two months (31 vs 48%; p=0.016) and at one year (19% vs 38%; p=0.009).

“Although the primary objective of noninferiority for trastuzumab monotherapy was not met, the observed loss of survival without chemotherapy was less than one month at three years, so this supports the use of trastuzumab monotherapy in this group of older patients with HER2-positive early breast cancer,” says Sawaki.

A sub-study of RESPECT did not show any negative effects of chemotherapy on cognitive functioning, which was reassuring as some older patients prefer to have combination treatment, explains Sawaki.

As yet unpublished GA data from patients in the RESPECT trial showed that comorbidities, increased creatinine, and Hospital Anxiety and Depression new Score (HADS) all affected AEs; comorbidities, reduced neutrophil count and Philadelphia Geriatric Center (PGC) Morale Scale new score affected DFS.

A validation study of geriatric assessment using the G8 score is now being carried out to confirm the probability of predicting AEs and prognosis in patients over 70 years with operable breast cancer. Sawaki reports that, as of July 2022, 646 patients had been recruited to the study, in which G8 assessment is carried out at baseline and after three months of treatment according to investigator and patient choice. Observational outcomes include DFS and overall survival (OS).

A further ongoing study of breast cancer treatment in older patients (65 years and over) in Japan is the non-inferiority, Phase 3 HERB TEA trial. Patients with advanced HER2-positive breast cancer are being randomised to docetaxel, trastuzumab and pertuzumab or T-DM1, and 126 patients had been recruited by July 2022.

Future breast cancer trials in older patients

If positive, APPALACHES may set a new standard of care for older patients with ER-positive breast cancer, but what of those with other forms of the disease? Wildiers would like to see studies in older patients with HER2-positive disease and also in those with metastatic disease.

“We need studies that will test dosing and pharmacodynamics of breast cancer treatments in older patients to find out if we can start with lower doses and uptitrate slowly so that treatment is better tolerated. Doctors already do this but we need to investigate it properly so that we are using evidencebased dosing schedules,” he says.

Building on this approach to better understand how older patients respond to different dosing schedules, Biganzoli is involved in metabolomic research to predict the toxicity of chemotherapy in different patients.

“Blood samples from patients involved in geriatric assessment studies are being analysed to see if we can identify a metabolic signature that is predictive of severe toxicity in older patients with breast cancer and other tumour types. Implementing metabolomics in clinical practice will be quite complex, but the metabolomic research is a first step,” says Biganzoli.

She also wants to find out if genomic research can be used to identify a patient’s ‘epigenetic clock’ to see if that can predict their biological age more effectively than current geriatric assessment and whether this will give information about their risk of treatment toxicity.

Battisti believes that, in planning future clinical trials with older patients, investigators and sponsors should ask themselves two questions in order to become more inclusive of older patients:

“Are they trying to investigate the role of new treatments in patients who are well despite their age or are they wanting to investigate the impact of optimising treatment in order to get good outcomes while limiting toxicity for frailer, older patients? In both cases, including GA will help them find the patients they need,” he says.

He also supports pragmatic designs for trials of older patients, for example, with fewer hospital visits and interventions that discourage some older patients from taking part. Moving forward, he would like to see studies investigating whether or not older patients with locoregional breast cancer need radiotherapy and if systemic treatment de-escalation is possible in the metastatic and advanced setting. In addition, he would like to see studies of non-chemotherapy options in older patients with triple negative breast cancer based on a better understanding of the biology of the disease, and more research on antibody drug conjugates and immunotherapy in older patients.

“We also need to investigate the economic impact of an integrated oncogeriatric approach to find out if – as I believe we will – we can reduce costs if we introduce GA and achieve more targeted, precision oncology in this age group,” concludes Battisti.

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