Breast cancer is the second leading cause of cancer-related death in women worldwide. Due to the prevalence of polypharmacy, which is the use of more medications than clinically necessary and at least one unnecessary drug, elderly cancer patients with comorbidities are more likely to experience adverse drug events, drug-drug interactions, increased mortality, and hospitalizations [1] . A group of enzymes, known as cytochrome P450s (CYPs), serves as catalysts for the oxidation of many endogenous compounds and xenobiotics [2] . CYPs, the main enzymes in drug metabolism and bioactivation, mediate about 75% of all drug metabolic processes. CYPs 1, 2, and 3 family members are the primary contributors to the oxidative metabolism of more than 90% of therapeutic drugs among the 57 functional human CYP genes and 58 pseudogenes [3] .

Traditional, time-limited cytotoxic chemotherapy regimens are replaced with continuous oral therapy with targeted drugs as part of an anti-cancer approach. Patients who may have comorbidities are prescribed targeted treatments for extended periods. Drug interactions can occur at all dosage levels, and either overdose or undertreatment can have serious clinical outcomes [4] . The median time to oral chemotherapy receipt from the day the order was written was eight days [4] . The provider performed toxicity checks at 30, 60, and 90 days for 80%, 65%, and 48% of the patients [5] . Potential drug interactions were observed in 55% of the patients [5] —drug-drug interactions through the use of experimental systems in drug development. Recent advances in silico approaches, such as pharmacokinetics modeling methods based on cheminformatics and physiological evidence, have been used to assess DDI potential but face challenges concerning reliability and accuracy [6] .

With prevalence rates ranging from 23% in the United States to 63.2% in Türkiye among women over 65 years of age, polypharmacy increases with age and varies by nation [1] . Strategies must be developed to minimize unnecessary drugs in older women with cancer to improve their clinical outcomes [7] . Cancer patients use complementary and alternative medicine (CAM) to enhance survival rates, reduce side effects from therapy and cancer symptoms, and improve immune function [5] . Drug interactions are a major concern in cancer treatment, and they may impact plasma drug monitoring, which is crucial to optimizing antitumor action and reducing drug toxicity to normal tissue [8] . Several instances of these interactions between cytotoxic drugs have been discussed in the literature, including those involving methotrexate and NSAIDs and irinotecan and St. John’s wort [4] .

An important class of anti-cancer medications is kinase inhibitors (KIs). Many are human cytochrome P450 (CYP) substrates and inhibitors, increasing the risk of undesirable drug interactions [3] . Eleven kinase inhibitors are approved by the U.S. Food and Drug Administration [9] . In a study, the impact of a library of K-I, which included 11 KIs that have received FDA approval, was tested on human CYP1A2, CYP2D6, 2C9, and 3A4. Inhibition of CYP1A2, 2D6, 2C9, and 3A4 was significantly inhibited by 80 compounds, or around 13% [1] . These findings imply that many KIs can operate as CYP inhibitors, and more research is required to determine how they can affect patients’ health [1] . Computational methods like molecular coupling offer insights into drug-enzyme interactions, aiding in drug design and toxicity prediction, but improvements in virtual screening are necessary for more accurate metabolism site prediction [10] .

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6 inhibitors) have demonstrated remarkable efficacy in treating advanced breast cancer, particularly when combined with endocrine therapy. However, their metabolism involves CYP3A and SULT2A1 enzymes, necessitating careful consideration of potential DDIs with other medications metabolized by these enzymes. The three approved CDK4/6 inhibitors exhibit varying adverse effect profiles, with abemaciclib associated with higher rates of diarrhea and fatigue, while palbociclib is linked to neutropenia and gastrointestinal toxicity. Effective management of these side effects through dose adjustments and close monitoring is crucial for successful treatment outcomes [11] - [13] .

The enzymes CYP3A and SULT2A1 are involved in the metabolism of the three CDK4/6 inhibitors, and CYPA3A mediates the liver metabolism of ribociclib. One of the three inhibitors should not be used with a strong (such as phenytoin or clarithromycin) or moderate (such as modafinil, abemaciclib, or modafinol) CYP-3A inhibitor. The use of CYP 3A inhibitors may increase, which may result in increased toxicity or reduced efficacy for some medications [13] . Compared to the other two CDK4/6 inhibitors, abemaciclib exhibits a higher rate of diarrhea and tiredness but a lower rate of hematologic side effects, such as neutropenia and nausea. Neutropenia, leukoencepenia, fatigue, and nausea are the most frequent adverse effects of Palbociclib. The most frequent grade 3/4 side events in the MONARCH-1 study were hypertension, elevated levels of ALT/AST, and lymphopenia [14] .

Neutropenia and gastroinotoxicity are the main adverse effects of CDK4/6-inhibitor-based combination therapy, such as Palbociclib. However, there are some variances for other drugs. In contrast to chemotherapy, toxicity can be controlled by changing the dose. Successful treatment depends on early and adequate monitoring, regular clinical evaluations, and control of adverse effects [13] .

In a study involving patients receiving palbociclib in conjunction with endocrine therapy, 38 patients (38.0%) required dosage adjustments. The majority of these adjustments (81.6%) were implemented during the second and third treatment cycles. The most prevalent treatment-related adverse events necessitating dosage modification were neutropenia (grades 3 - 4, 54.8%) and mucositis (grades 1 - 3, 9.5%). The most frequent dosage modification among these 38 patients was a reduction from the standard 125 mg daily dose of palbociclib to 100 mg daily (65.8%). Less frequent adjustments included delaying or restarting the full dose or modifying the administration schedule (7.9%) [15] .

One of the most reported adverse effects of TKI therapy with a TKI is diarrhea, a typical side effect of many cancer therapies. Depending on the drug, the reported incidence of all-grade diarrhea for various TKI in Breast cancer ranges from 18 to 95% [16] .

The mainstay of the pharmacological therapy for uncomplicated mild to moderate diarrhea is loperamide, which is recommended in the prescription of advice both as prevention and after the beginning of diarrhea [17] . When diarrhea does not disappear despite the use of antidiarrheal medications, therapy should be postponed until grade 1 diarrhea has occurred [18] . Patient education is essential to help patients recognize the symptoms and indications of diarrhea and emphasize the urgency of immediate treatment [19] .

The widespread use of complementary and alternative medicine (CAM) among cancer patients underscores the need for healthcare providers to be knowledgeable about these therapies and their potential interactions with conventional treatments [20] . Cancer patients can reduce the various side effects because of chemotherapy due to the link between natural products and ACD [5] . Due to the interaction between the drug and the natural substance, this relationship involves risks that outweigh the actual benefits [5] . While CAM can offer benefits in managing side effects, the risk of drug-herb interactions, particularly those affecting CYP enzymes involved in drug metabolism, cannot be overlooked. These interactions can alter drug pharmacokinetics and pharmacodynamics, leading to therapeutic ineffectiveness or toxicity [5] .

The amount of medication that reaches the target site may change due to metabolic interactions, leading to therapeutic ineffectiveness or even toxicity from overdose [21] . The supply of phytochemicals and the cytochrome system together is not recommended and can be detrimental. One of the most frequent alterations in these interactions is the potential activation or inhibition of CYPs that metabolize ACDs [21] . Prebiotics, probiotics, fungi, and plants should no longer be considered separate dietary supplements but possible adjuvants in traditional pharmacological therapy. Red ginseng and ginger help reduce the most typical gastrointestinal adverse effects of ACD use, nausea, and vomiting (6-gingerol) [5] .

A study finds that CAM therapies can be cost-effective for various conditions, and it emphasizes the importance of economic evaluations to guide evidence-based clinical practice and health policies. Furthermore, the paper points out the need for better quality data on CAM therapies, which the lack of participation of practitioners in research can hinder [22] .

Polypharmacy is a prevalent concern among elderly cancer patients, often exacerbated by comorbidities. This increases the risk of DDIs and adverse drug events (ADEs) due to competition within the CYP enzyme system, altered drug metabolism due to comorbidities, and increased sensitivity to side effects in older patients. Complex medication regimens can also lead to confusion and errors. Proactive medication management, patient education, and minimizing unnecessary drugs are crucial in mitigating these risks and improving treatment outcomes for this vulnerable population [23] .

In a study between the older and non-elderly groups, the prevalence of comorbidity and polypharmacy in breast cancer patients were identified and compared. The most frequently reported comorbid conditions were arthritis, hypertension, and diabetes. The comorbidity was comparable to population reports and previous breast cancer research. The prevalence of gastrointestinal disorders was relatively high in both groups. This study is the first to highlight the importance of polypharmacy in patients over 65 years of age. Control groups without cancer had a lower frequency of comorbidity than older people with cancer. According to this study, only two individuals had no comorbid conditions, while up to 99% of patients 65 and older had at least one. The senior group had significantly higher levels of comorbidity (p = 0.001). The study observed a higher prevalence of several chronic conditions in elderly individuals compared to their younger counterparts. These conditions included diabetes, hypertension, gastrointestinal disorders, heart disease, and hyperlipidemia.

Furthermore, aging adults were more likely to experience asthma, depression/anxiety disorders, respiratory diseases, and musculoskeletal conditions. These findings have been frequently demonstrated in the historical process and are compatible with the literature. Research reveals that the elderly population used more medications on average, including PPI, ACEI-ARB, diuretics, beta-blockers, calcium channel blockers, anti-aggregant/anticoagulant, oral anti-diabetics, insulins, NSAID, inhaler treatment, vitamin D or/and calcium, bisphosphonates, and other pharmaceuticals. The incidence of drug usage was as expected when comorbid disorders were considered [1] .

In another study, polypharmacy is brought on by the rise of elderly patients and/or people with both cancer and other chronic diseases [4] . Since cytochrome P450 enzymes are primarily responsible for the metabolism of TKI and mTOR inhibitors, the danger of drug-drug interactions (DDIs) becomes a clinically significant concern. Depending on these DDI, exposure to anti-cancer drugs may vary [4] . Polypharmacy (multiple medications) is common in elderly cancer patients, who often have comorbidities. This increases the risk of DDI and ADEs due to:

These factors can lead to severe ADE, hospitalizations, compromised treatment, and worsening quality of life. Proactive medication management, patient education, and minimizing unnecessary drugs are crucial.

Antimetabolites. In one of the first cancer drug families, antimetabolites only include tiny compounds as their constituents. The prototypical folic acid analog methotrexate can be made worse by the nephrotoxic drug cisplatin—the failure to synthesize DNA and RNA results in hepatotoxicity [24] . A prominent example of a pyrimidine analog with negative consequences is 5-fluorouracil (5-FU), which can cause bleeding, leukopenia, thrombocytopenia, and other GI problems. However, the method of administration and the duration of therapy affect these toxicities [24] .

For women under 50 years of age and those between 50 and 69 years of age, chemotherapy lowers the yearly mortality rate from breast cancer by 38% and 20%, respectively. However, with four rounds of doxorubicin and cyclophosphamide treatment, there is a known risk of cardiotoxicity, with 17% of patients experiencing cardiac problems [25] .

Peak exercise SV and CO, as well as skeletal oxygen utilization, are reduced in post-anthracycline-treated BC Survivor women compared to matched controls. According to a mediation study, more significant myocardial fibrosis was associated with poorer exercise capacity and lower peak VO2. An overlooked factor in women with and without breast cancer’s cardiovascular risk is fatty infiltration of the thigh muscle [26] .

The BILCAP study compared adjuvant capecitabine with observation in patients with biliary tract cancer who underwent surgery with curative intent. Although the primary endpoint of overall survival did not reach statistical significance, the sensitivity analyses showed benefits in overall survival and recurrence-free survival [27] . Deferred recurrence occurred in the capecitabine group, and long-term survival analyses will be reported once five years of follow-up have been met. Adjuvant capecitabine improved overall survival compared to observation following surgery for biliary tract cancer, with a median overall survival of 24 months in the capecitabine group and 17 months in the observation group, suggesting a 7-month increase in OS with capecitabine treatment. The limitations include its long recruitment period of 10 years and the evolving approaches to clinical trials during this period [27] .

Alkylating Agents. A nitrogen mustard-type alkylating agent called cyclophosphamide is associated with myelosuppression, neutropenia, anemia, and thrombocytopenia. Small molecules such as DNase, p53, and MAP kinase are also included in this class of cancer drugs. Black-box warnings for nausea and vomiting associated with cisplatin can be avoided using antiemetic medications [24] .

The study found that low-dose CPA-induced hyponatremia was relatively common in breast cancer patients, but it usually resolved without any specific treatment [28] . Researchers identified age and pretreatment serum sodium levels prior to treatment as independent risk factors for hyponatremia. However, selection bias is possible since this was a single-center study with a small sample size. Therefore, more large-scale studies are needed to confirm these findings and assess the clinical significance of low-dose CPA-induced hyponatremia in breast cancer patients [28] .

The loss of appetite results in a decrease in BMI, which is beneficial in one aspect, as a research paper found that a higher body-mass index (BMI) was significantly associated with increased mortality rates due to breast cancer in women. The study also estimated that current patterns of overweight and obesity in the United States could account for 20% of all deaths from cancer among women [29] .

Antimitotic Agents. Breast cancer is one of many solid tumors that can be treated with docetaxel. Patients’ metastatic, radiation and neoadjuvant results can be improved. Patients with hormone receptor-positive or hormone receptor-positive breast cancer at high risk of the disease returning may consider adjuvant chemotherapy. The Western Hemisphere has seen a significant decline in cause-specific mortality from breast cancer due to adjuvant systemic chemotherapy [29] . The findings suggest that paclitaxel plus bevacizumab combination therapy may be a viable option for women with primary breast cancer, as it significantly improved progression-free survival and objective response rates compared to paclitaxel alone [30] .

Although overall survival rates between the two treatment modalities were similar, it is crucial to consider the potential risks associated with specific modern treatments, such as accelerated partial-breast irradiation and intensity-modulated radiation therapy, mainly when their use may only result in minor improvements in overall survival [30] . The study also highlights the clinical importance of targeting the VEGF receptor pathway and the potential utility of angiogenesis inhibitors, such as bevacizumab, in the treatment of primary breast cancer. These findings may have significant implications for the development of future therapies in this area [30] .

One of the cytotoxic drugs that commonly induces acute infusion responses is docetaxel. Typical “standard” and “classical hypersensitivity” reactions are among them (i.e. angioedema, urticaria, wheezing, stridor, anaphylaxis, and cardiorespiratory). Before infusion, premedication with glucocorticoids and antihistamines helps reduce the severity of these responses [31] .

Myelosuppression reduces white cell count (or neutrophil count) after chemotherapy treatment and can occur 10 - 14 days after initial administration. Patients who develop this condition are at increased risk of serious infections and often require hospitalization, resulting in a dose reduction of docetaxel. Docetaxel treatment commonly causes fluid retention that manifests itself as pericardial effusion, pleural effusion, and extremity edema. One of the hypothesized causes for this unfavorable effect is enlarged capillaries, which cause fluid to leak into the tissue around them. Therapy with diuretics can minimize the severity of fluid retention and relieve symptoms [31] . Docetaxel, a chemotherapy drug, is associated with several adverse drug reactions (ADRs), including neutropenia, anemia, thrombocytopenia, peripheral neuropathy, and alopecia. Patients should report any new symptoms during treatment to ensure prompt treatment. Long-term effects result in tingling, numbness, and loss of sensation, categorized into sensory and motor neuropathy [29] . In docetaxel treatment, early detection of symptoms, followed by a delay in medication or dosage decrease, helps to reduce its ADRs (adverse drug reactions). The main clinical signs are numbness, tingling in the hands and feet, and reflex loss. Taxane-induced neuropathy may benefit from symptomatic relief with anticonvulsants such as gabapentin [31] .

Hormonal Therapy. Hormonal therapy, although practical, faces adherence challenges, with approximately one-third of patients discontinuing treatment before the recommended 5-year duration. This premature cessation is primarily attributed to adverse symptoms associated with estrogen deprivation. Among these, myalgias and arthralgias are particularly prevalent, affecting up to 30% of women receiving aromatase inhibitors (AIs) therapy. Consequently, it is imperative that patients initiate AI treatment with a baseline assessment for osteopenia and osteoporosis, given the increased risk of bone loss associated with these medications [32] .

According to studies, women who produce more estrogen have a higher chance of developing breast cancer. Stimulation of breast cell proliferation by the estrogen receptor (ER) and the conversion of estradiol to genotoxic metabolites have both been suggested as potential explanations for the increased risk. The research is based on the idea that genotoxic and receptor-mediated mechanisms contribute to breast cancer. The enzymes required to convert estradiol were first shown to exist in MCF-7 breast cancer cells and normal breast tissue in mice transfected with aromatase. The effects of castration-induced estrogen depletion and the role of the estrogen receptor (ER) alpha on tumor development were then studied in ER knockout/Wnt-1 (ERKO/Wnt) transgenic rats. Lastly, in noncastrate, ER KO/Wnt mice later evaluated the impact of an aromatase inhibitor on tumor incidence [33] .

Studies have shown that the risk of breast cancer recurrence is significantly reduced in patients who suffer vasomotor symptoms within the first three months of therapy. The dependence on the reported toxicity of physicians is a significant obstacle and may have led to underestimating the burden [34] . Data on the genetic factors that influence the AI response are few, especially in the front-line metastatic situation. Although the polymorphisms CYP19A1 and CYP1A2 are alluring response indicators, little data supports their therapeutic value. To clarify the function of these genes, more research is needed in prospectively recruited breast cancer patients [32] .

Aromatase inhibitors are only used in postmenopausal cases, while LHRH analogs may also be prescribed to premenopausal women. Around 50% of hormone-dependent cancers become resistant over time, but certain molecules such as Palbociclib and Everolimus have effectively reversed this resistance [35] . Tamoxifen (SERM) is a selective estrogen receptor modulator that increases the risk of posterior subcapsular cataracts. It also affects perception similarly to aromatase inhibitor (AI) but in an age-dependent manner, suggesting that a change towards lower levels of estrogen activity is more critical than low estrogen activity itself [36] .

Immunotherapy Agents. Combining pertuzumab with trastuzumab, which each inhibits a separate domain of the HER2 receptor, efficiently treats HER2-positive breast cancer [37] . According to clinical trials, pertuzumab is typically safe and beneficial for patients, although it can occasionally result in severe cardiac damage [25] [37] . The most common but often mild side effect is diarrhea. Some researchers suggested that pertuzumab may not significantly assist patients with small primary tumors. In general, the study emphasizes the need for careful patient selection and monitoring by highlighting the possible advantages and disadvantages of combination therapy targeting particular subtypes of breast cancer [37] .

In the TRYPHAENA study, the anthracycline regimen was associated with more significant febrile neutropenia than the nonanthracycline regimen and secondary leukemia and cardiotoxicity. The percentage of patients receiving G-CSF support between the two therapy groups was relatively similar [25] . Although they still showed unfavorable toxicity levels, nonanthracycline chemotherapy regimens for breast cancer were shown to have a more favorable toxicity profile. Most of the patients in both groups had grade 2 or worse neuropathy, and treatment techniques are being researched. The typical and bothersome side, diarrhea, tends to increase when administered with a taxane-carboplatin [25] .

A study analyzed 1,045 breast tumor samples to identify differential immune signatures associated with survival using gene expression profiling techniques. They established a TAIG (tumor-associated immune gene) risk model to predict poor survival outcomes for patients with advanced pathological stages or higher stages of AJCC-TNM based on high TAIG levels correlated with these clinical characteristics. Additionally, analysis of the TIMER database revealed adverse associations between TAIG levels and various types of infiltrating lymphocytes. This research provides valuable information on potential targets for immunotherapy treatment options and highlights the importance of understanding the interactions between different components within the tumor microenvironment [12] .

Trastuzumab is a monoclonal antibody used to treat metastatic breast cancers that overexpress HER-2. HER-2 is a member of the EGFR family that regulates cell proliferation and survival. Trastuzumab is rarely associated with significant skin toxicity, unlike anti-EGFR targeted therapies, and this may be explained by the lack of detectable functional HER-2 heterodimers in human keratinocytes, which is different from the EGFR dimerization.

Breast cancer treatment necessitates a multifaceted approach, particularly for elderly patients at risk of polypharmacy and DDIs. Understanding CYP enzymes’ role in drug metabolism is crucial for both conventional and CAM therapies. While CAM offers potential benefits, healthcare providers and patients must be aware of potential interactions with conventional drugs. Research should focus on investigating CAM effectiveness and potential metabolic interactions.

Kinase inhibitors (KIs), a vital class of anti-cancer medications, often interact with CYP enzymes, highlighting the need for careful research to predict potential DDIs. In particular, cyclin-dependent kinase 4/6 inhibitors (CDK 4/6) have shown remarkable efficacy in breast cancer treatment. However, close monitoring of adverse effects, such as neutropenia and gastrointestinal problems, is essential to manage DDIs and dosage adjustments. Patients should be fully informed about possible side effects like diarrhea and informed about prompt symptom management.

The widespread use of CAM highlights its potential benefits, but healthcare providers must be knowledgeable about these modalities to ensure safe integration with conventional therapies. Research should prioritize investigating the effectiveness of CAM alongside the potential for metabolic interactions that could affect the efficacy of anti-cancer drugs.

Polypharmacy in elderly cancer patients underscores the need for rational drug use, robust clinical follow-up, and medication awareness programs. Addressing polypharmacy can significantly improve treatment outcomes.

In conclusion, successful breast cancer management requires a multifaceted approach. Healthcare providers must be informed about the complexities of drug interactions, including those involving CAM, to personalize treatment plans, optimize results, and minimize adverse events. More research is needed to understand the interaction between conventional and complementary therapies fully and to develop strategies that reduce the risks associated with polypharmacy, especially in older patients.