Sex Differences Could Shape Future Cancer Immunotherapy

Do sex differences in biology affect how cancer immunotherapies will work in individual patients and how their side effects will be? Cancer immunotherapy has transformed the treatment of many cancers by leveraging patients’ immune systems. Not all patients, however, will equally benefit from these emerging therapies, and whether or not a patient is male or female may be one of the factors that determine whether or not he or she receives benefit, or experiences side effects. The differences between the sexes in chromosomes, hormones, immune cells, metabolism, body composition, organ function, and virtually all other biological parameters are well documented and growing. The evidence base is rapidly accumulating regarding how these differences may affect how cancer patients respond to different cancer immunotherapies. There is growing interest among oncologists, payers, and policy-makers to take a sex-aware approach to the use of these expensive cancer therapies with the goal of enhancing benefits while decreasing harm.

It’s time to make sex-aware immunotherapy not an optional tweak to treatment but a standard part of the game to make immunotherapy better and safer for everyone. Using sex as an important perspective in preclinical models and in the design of clinical trials could allow researchers and clinicians to identify patients most likely to benefit from treatment, monitor toxicities, incorporate endocrine and fertility services into care and design trials and clinical practice that reflect these findings. The possibilities for long-term implications for clinical trial design, clinical guidelines and reimbursement and practice translate to what happens in clinical trials versus routine clinical practice.

Why It Matters

1) Biology can change both efficacy and toxicity

Sex differences in the immune system may impact the effectiveness of immunotherapy for cancer. On average, females develop more effective anti-tumor immune responses that are capable of more strongly controlling tumor growth, but at greater risk for life-threatening immune-related adverse events (IRAEs) in which the immune system attacks a healthy organ or tissue. In contrast, some studies have found that males may mount treatment-specific immune responses that can predict both the duration and level of inflammation of the treatment-induced response as well as recovery from toxic side effects. These population-level insights highlight both the potential for great benefit as well as harm with immunotherapy.

Hormones can influence the immune system and potentially how patients respond to immunotherapies, such as many different types of immune checkpoint inhibitors. Estrogen, progesterone and testosterone can all affect immune cells, inflammation and antigen presentation by modulating key signaling pathways. But these hormones change dramatically at different times in a person’s life – at puberty, during and after pregnancy, and around the time of menopause. This means a person’s immune set-point could change at different times in their life, potentially meaning that the same therapy will have different effects based on the person’s reproductive stage, level of ovarian function or androgen levels.

Genetics and chromosomes add an extra dimension to our understanding of the immune system as many genes related to the immune response are located on the X chromosome and show different levels of gene expression in males and females. This affects the diversity of immune cells, the cytokine profile and tolerance of self which can all prevent autoimmunity, but can also show individual variability. However, good immune surveillance of cancer is often effective in controlling or killing the tumour but at the same time can pose a risk to normal organs such as the thyroid, lungs, liver, bowel, skin, joints and pituitary gland.

2) Side effects are not minor and can have a long lasting impact on your health.

While most immune-related adverse events are reversible and mild in degree, some can be serious, life-threatening and even chronic. The more common ones include thyroid dysfunction, colitis, pneumonitis, hepatitis, arthritis, rash and fatigue. Some of these may remit within a year of treatment completion, but others are persistent and require chronic management on hormones or through a specialist. It would be useful to know if there are differences between the sexes in incidence and severity of these toxicities, in order to design monitoring and counseling schedules for patients accordingly.

Management and follow-up of long-term survivorship needs will vary by type of toxicity and organ/system involved. Endocrine toxicities may require long-term follow-up for development of hypothyroidism, adrenal insufficiency or insulin dependent diabetes. Immune related complications to the heart, brain, lungs, etc. are less common but can be serious and potentially require rehabilitation services and/or surveillance imaging. Patients and their families should be counseled that immune toxicities are more common than ever, due to the increasing use of immunotherapy (solo or in combination) as first line treatment of many cancers, and even in the adjuvant setting where patients are being cured but at risk for treatment toxicities.

3) Cost and value – as seen from different perspectives. Who do you think benefits the most from a good sales forecasting process? Your customer probably hopes that it is him.

Immunotherapies are expensive treatments and their value depends, in significant part, on their ‘real world’ efficacy and toxicity. As a consequence, there are likely to be sex differences in both the probability of response and in the probability of experiencing treatment-related toxicity. The cost-effectiveness of cancer immunotherapies therefore may differ in female- and male-patients. This, in turn, is likely to result in differing volumes of emergency visits, hospitalizations, steroid courses, referrals, imaging studies and laboratory tests that translate into post-treatment costs, no matter how modest they may be.

Payers and health systems require accurate stratified evidence not to miss out on the benefits of the drug but to avoid both underuse and overuse in certain subgroups. In subpopulations where a particular regimen is unlikely to benefit patients, clinicians could consider an alternative treatment sequence or combination regimen(s) or use biomarkers to select patients most likely to benefit from treatment. In subpopulations where patients are more likely to experience severe toxicity, closer monitoring and early intervention pathways could help to prevent severe toxicities, treatment pauses and improve the patient experience. An sex-aware approach to evidence use supports smarter (not unfair) allocation of limited health resources.

4) The evaluation should include an assessment of equity, reproductive health, and the broader social context.

Differences between men and women must be taken into consideration when making cancer therapy decisions. If the decision is one that will impact the patient’s ability to have children, be pregnant, or have a family, the provider should be aware of these desires and consider them when choosing therapy. Some cancers and therapies (like immunotherapy in addition to chemotherapy or radiation) may specifically impact these interests and need to be discussed to allow patients to weigh their wishes with potential risks and benefits. In addition, patients of reproductive age will need to be counseled regarding use of contraception and the timing of pregnancy for optimal immune modulation. As more cancer therapies are administered, more questions have arisen regarding the use of cancer therapy during pregnancy. Unfortunately, data have been limited, and as more cancer therapies receive FDA approval and enter clinical use, more information regarding the risks and benefits of cancer therapy during pregnancy is emerging.

Beyond the biological effects of cancer and its therapies, interactions between social factors and biology further influence access to care and patient outcomes through detection, adherence to treatment and follow-up, and many other domains. In addition to the effects of care and disease on body and mind, issues of caregiving responsibilities and resources, as well as travel time and distance to oncology care, affect both patient outcomes and treatment choices. The sex-aware framework, therefore, must include consideration of issues that are beyond biology alone in terms of safety, efficacy, and toxicity.

Who It Affects

Patients receiving immunotherapy across cancer types

As the number of novel cancer therapies under development increases, it is critical to evaluate sex differences in therapeutic efficacy. Immune checkpoint inhibitors, CAR T-cell, bispecific antibodies, cytokine based therapies, and cancer vaccines will affect men and women differently in terms of degree and duration of therapeutic effect including depth and timing of response, duration of remission and need for additional therapy. These considerations are highly relevant to patients with melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer as well as subsets of breast cancer and hematologic malignancies.

Patients with a history of an autoimmune disease or vulnerable organs may be inherently more difficult to treat. In addition, many other medical conditions, including baseline thyroid disease, inflammatory bowel disease, lung disease, hepatitis or diabetes can potentially affect the risk for certain toxicities. Given that sex can influence immune activation, it is reasonable to expect that patients with comorbid conditions may react differently to cancer treatment than healthy patients, and that this may affect the choice of chemotherapy, monitoring for toxicities, and the threshold for referral to other specialists.

Clinicians and multidisciplinary teams

The oncologist needs to consider risk-benefits that are specific for sex and age in the process of decision making about the choice of chemotherapy and/or radiotherapy. The oncologist and patient and families also need to consider expectations regarding symptoms that might occur. The health-related quality of life (HRQOL) expectations as well as the plans for the detection of life threatening side effects such as cardiac toxicity, symptom clusters and secondary malignancies (i.e. acute myeloid leukemia in patients who have received alkylating agents) need to be considered. The baseline level of endocrine, cardiopulmonary and autoimmune symptoms and medications need to be recorded and compared at subsequent visits. Furthermore, specific plans for intervention and referral need to be addressed prior to the initiation of oncology therapy.

Primary care physicians and specialists in survivorship and toxicity management are playing an increasingly important role. Endocrinologists will manage patients with thyroiditis, hypophysitis, adrenal insufficiency and diabetes. Patients with immune-related colitis will be referred to gastroenterologists, those with pneumonitis to pulmonologists. Dermatologists, rheumatologists, cardiologists and neurologists will be consulted based on the pattern of toxicity. Looking at sex differences in the experience of patients and families can help healthcare providers anticipate and proactively address certain concerns.

Pharmacists and nursing staff play important roles in ensuring safe administration of thiouracil and in detecting its toxicity. Generally, nursing staff are the first to identify early toxicity as they conduct triage calls and screenings. The pharmacist would then review for potential drug interactions, manage the decrease in steroid taper, as well as teach patients with hyperthyroidism about potential toxicity. Potential sex differences in the timing or in the pattern of toxicity could be taken into consideration when revising triage protocols and patient education materials.

Payers, policymakers, and research funders

Health plans and hospitals that care for patients on immunotherapy want to know the cost and pattern of use of these costly drugs, which are increasing rapidly in volume. The Coverage Policy sets forth the terms and conditions of coverage for immunotherapies, assuming that the treatment is beneficial for most patients and poses reasonable risk for most patients. However, evidence of benefit for some of these treatments comes from clinical trials that did not collect outcomes data on women, or that did not have policies and procedures in place to manage toxicities that differ by sex. Future programs for gathering real-world evidence, measuring quality and value, and finding value in cancer care through the use of immunotherapy are likely to track outcomes by sex.

Regulators and funders have a crucial role to play in improving the evidence base on sex differences in medicines. Currently, too many trials enrol too few men or women, or fail to report relevant outcomes separately for each sex. By raising the bar for trial design and reporting of results on sex, it should be possible to produce more reliable evidence that translates better to clinical practice for both women and men.

What Changes

1) Trial design and reporting will become more sex-aware. Many current clinical trials are now realising the flaw in their trial design with regards to sex differences.

The Sex disaggregated analyses will no longer be seen as an add-on to clinical trials. These analyses need to be planned for and studies should ensure that they include sufficient numbers of men and women to adequately explore differences and similarities. The studies also need to take into account the hormonal status of women (e.g. premature menopause, HRT, hormone ablation) as it significantly affects immune response.

Future biomarker studies will need to include sex as a biologic variable. In particular, predictive biomarkers such as tumor mutational burden, PD-L1 expression, microsatellite instability, and gene signatures related to the immune and tumor environments and levels of circulating immune cells will need to be studied in both women and men. A marker that predicts benefit in one group of patients may have less or even opposite predictive value in another group. In addition to the risk of incorrect classification, failing to validate biomarkers for treatment decisions in women and men may result in worse treatment outcomes for patients of both sexes. Inclusion of sex-aware biomarker validation in oncology trials will be necessary to optimize treatment decisions for women and men with cancer.

2) Progresses to more individualized clinical care (eg, monitoring and counseling programs).

In the next few years, sex will need to be incorporated into shared decision-making in a practical, patient- and family-centered manner. This means that patients and their clinicians will have a clear understanding of how sex may affect treatment outcomes and toxicity, as well as how other individual factors — including information about the specific type of tumour, biomarkers, any medical conditions that the patient has, and his or her general health — will affect these same outcomes and toxicities. In order to make informed decisions, patients and their clinicians will need to have a sense of how sex might affect outcomes and toxicity for their specific diagnosis, without making generalizations about women and men with certain types of cancer.

Preventable harm can be decreased by tailoring monitoring and treatment of individual patients on the basis of their predicted level and severity of toxicity. This might include more frequent monitoring of endocrine labs for patients predicted to have high endocrine toxicity, earlier evaluation for lung toxicity in patients who are prone to it, and quicker evaluation and referral for patients with gastrointestinal symptoms. In addition, using a symptom checklist and educating patients and families about early warning signs of immune toxicity can help prevent delayed treatment for patients experiencing these symptoms.

3) Future supportive care pathways will incorporate additional reproductive and endocrine patient care strategies.

Fertility and reproductive counseling should be introduced earlier in the overall treatment plan. Discussion and planning for options to preserve fertility prior to initiation of cancer therapy, as well as timing of conception or use of contraception after cancer therapy, should occur particularly in younger patients for whom curative intent is possible and in whom treatment includes immunotherapy. Documentation and referral of patients for fertility preservation also need to be addressed to ensure timely initiation of cancer therapy and to allow patients to make informed decision regarding reproductive options.

Future long-term survivorship plans will need to address chronic effects of immune changes. Survivorship plans for long-term survivors should include endocrine follow-up and monitoring, vaccination recommendations for appropriate patients, screening for function of specific organs, management of chronic mental health effects, and coordination with the patient’s PCP and the oncology team. Sex-aware survivorship and long-term risk, as well as patient priorities.

4) Policy, coverage, and quality measures may evolve

Guidelines and evidence programs supporting guidelines are likely to report outcomes sex disaggregated in the near future. Health system dashboards to monitor and learn from the response to guidelines, including discontinuation, response, hospitalization, steroid use and toxicities may reveal critical deficiencies and inequities in treatment safety and outcomes before harm occurs. Monitoring outcomes for women and men separately could also reveal differences in efficacy and highlight disparities in access to potentially life-saving treatments for specific diseases.

As evidence emerges it is likely that the reimbursement and prior authorization policies and procedures will strive to organize this information in a stratified fashion in order to avoid unnecessary and unfair limitations. Similarly, the coverage models developed for these medications will require ongoing scrutiny to identify particular supportive services and/or follow-up tests that may be required for particular patient populations. This is all intended to ensure that the focus remains on optimal patient outcomes and safety and not on creating avoidable barriers to appropriate use.

Practical steps clinicians and decision-makers can take now

In addition to evaluating the quality of current evidence for immunotherapy to determine if there is evidence specific to sex, also evaluate the quality of evidence to determine if providers document baseline risk factors. Standardized intake templates and lab panels as well as standardized screening for symptoms in intake can help detect potential toxicity earlier. Staff and patients should receive education on early symptom recognition as well as clear pathways for urgent evaluation.

All patients should be made to fully benefit from the multidisciplinary treatment pathways, with minimal delay to the start of toxicity treatment. This includes access to rapid-access clinics, a standardized steroid regime, and referral to endocrine, pulmonary and gastroenterology services, being aware of sex differences and optimized for patient-specific risk.

The research leader should design the clinical trial to attempt to achieve balance in terms of enrolment numbers to the trial as well as to test prespecified subgroups. In this way, the results of the trial will be more valid and useful, contributing to better cancer care delivered more precisely and equally to all patients.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC11165033/