Diabetic Retinopathy: prevalence and associated risk factors amongst patients diagnosed with diabetes mellitus
September 23, 2024
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Breast cancer is a major global health concern, considering that it is the most often diagnosed cancer and the foremost cause of cancer death in women. There has been concern over its threat to women in various parts of the world, including the United States, Europe, and India. Gender and age have been identified as significant risk factors for breast cancer. The majority of breast cancer cases have been reported in women who have no family history of breast cancer, and these are the result of the aging process of general genetic mutations rather than inherited mutations.
Breast cancer is a highly heterogeneous cancer; therefore, the need for personalized medicines is rising over time. Traditional treatment methods are giving way to personalized medicine. In this white paper, we have focused on breast cancer threats in the US, Europe, and India, problems that are responsible for poor outcomes in breast cancer patients, and solutions to those problems by using personalized medicines. The large trials with a focus on personalized medicines for the treatment of breast cancer presented at ASCO 2019 are also discussed in this white paper.
Breast cancer is the most common type of cancer among women worldwide, and has beenbecoming a threat in healthcare. In 2018, there were 2 million new cases of breast cancer throughout the world. There were approximately 627,000 deaths that accounted for 15% of all cancer deaths in women.
In the United States (US), it is estimated that 268,600 new cases of invasive breast cancer accompanying 62,930 new non-invasive (in situ) cases will be there in 2019, and the estimated deaths will be 41,760 due to breast cancer. Breast cancer is also expected to account for 30% of newly diagnosed cancers in women in the United States. However, the survival rate for breast cancer is as high as 90%.
In Europe, new cases of breast cancer occur more than twice as frequently as new cases of other cancers. In 2018, the estimated incidence of breast cancer was 562,500. On average, 20% of incidences occur in women younger than 50 years; 36% occur at 50–64 years old; and 44% occur above this age. The estimated number of women who died from breast cancer in 2018 was 150,700.
In India, 162,468 new cases and 87,090 deaths were observed in 2018. According to the Indian Health Ministry, the breast cancer occurrence rate is as high as 25.8 per 100,000 women, and the mortality rate is 12.7 per 100,000 women. In men, breast cancer is rare, with an incidence rate of less than 1% (1 in 883). In India, the survival rate for breast cancer is low: only 66.1% of women diagnosed with breast cancer from 2010 to 2014 survived. Moreover, gender and age have been identified as significant risk factors for breast cancer, as women after menopause with increasing age are more susceptible to getting diagnosed with breast cancer than men.
Numerous studies on breast cancer have been conducted and continue to be conducted. These studies have revealed various risk factors that contribute to the origin of breast cancer. A few of these risk factors include getting older, genetic mutations, hereditary, previous treatment including radiation therapies, reproductive or menstrual history, dense breasts, and exposure ton diethylstilbestrol (drug used in US during 1940-1971 to prevent miscarriage).
There are some women who will develop breast cancer regardless of any other risk factors they are aware of. It is imperative to remember that risk factors do not guarantee disease development, nor are all risks equally harmful.
Gene mutations, inherited from the father or mother, are responsible for 5-10% of breast cancers. Among these mutations, BRCA1 and BRCA2 gene mutations are the most common. These genes are involved in the production of proteins that rebuild degraded DNA in normal cells. However, when mutated, these genes lead to abnormal cell growth, which is eventually the cause of cancer. Women with a BRCA1 or BRCA2 mutation have a lifetime risk of 72% and 69%, whereas men’s
risk rates are >1% and 6.8%, respectively. Women of younger ages have a higher risk of getting these gene mutations. About 85% of breast cancers develop in women with no family history of breast cancer. These are the result of the aging process or general genetic mutations, not inherited mutations.
The main reason that makes treatment outcomes poor is the heterogeneity of breast cancer. Heterogeneity in expressing established predictive and prognostic biomarkers, i.e., human epidermal growth factor receptor 2 (HER2) oncoprotein and hormone receptors should be the basis for treatment selection. The indicator of genetic tumor heterogeneity that is probed with multigene assays is molecular categorization, which aids in stratification into low- and high-risk groups for personalized treatment. Breast cancer has been categorized into five different molecular classes, as shown in the below figure; most of the breast cancer cases are hormone receptor positive (40-
60%).
Heterogeneity may be intertumor heterogeneity (differing among different patients) or intratumor heterogeneity (differing within each individual tumor). Out of these two, intratumor heterogeneity is the most significant barrier to successful cancer therapy.
In addition to tumor diversity, cancer patients or individuals with a high risk of getting cancer also have a diverse range of genetic characteristics. Together, all of these factors determine the risk of disease progression and therapeutic resistance.
Previously, tumors were treated with traditional treatment approaches such as radiation, surgery ,and/or chemotherapy, but currently, biomarker testing is helping oncologists with more personalized treatment options. Personalized medicines are one way to overcome these obstacles. Notably, before 2006, the expansion of biomarkers was highlighted by patient incidences of biomarkers such as HR-positive and HER2-negative breast cancer found in about 53% of postmenopausal patients. Even in early 2000, breast cancer was highly segmented, but the identification of the new BRCA1/2 genetic marker further categorized responders to specific treatments.
The type of treatment is evolving from traditional treatments to personalized medicine. In traditional methods, treatments were selected based on the location of the tumor and their number. But there was a big problem with this strategy because tumors arising from the same location have different genetic makeups. In clinical trials based on traditional approaches, patients having the same tumor origins are enrolled, and all patients are treated with the same medications. But now
there are advancements in the clinical trial designs, and personalized treatment strategies are part of those advanced clinical study designs. In clinical research, to implement a personalized treatment strategy, “basket and umbrella” study designs are gaining popularity. The combination of the basket and umbrella designs creates the “Super Umbrella Trials.” The figure below represents the basket and umbrella trials and what theyactually evaluate.
Personalized medicine is a treatment or prevention strategy in which individual variability in genes, lifestyle, and environment is considered. Although this approach is becoming more common, there are further advances in omics technologies to develop more precise approaches. Personalized treatment doesn’t mean the treatment is only for a specific person, but for a group of people who share the same characteristics. For e.g., premenopausal women with HER2-positive and lymph node-positive breast cancer as well as other groups with similar characteristics can benefit from personalized medicine. For this approach, a personalized treatment plan is chosen after understanding the genetic level of the patients.
The use of personalized medicine is making a big difference in cancer treatment and trastuzumab is a successful example of this. There are multiple copies of a gene called HER2 in patients with breast cancer, and these cancers often have a poor prognosis and are highly aggressive. The discovery of trastuzumab made a big impact on these patients, improving survival from 20 months to 5 years in women with advanced HER2+ breast cancer.
Healthcare is moving rapidly towards personalized medicine, and it helps in a thorough understanding of human physiology by understanding the genetic level and advancements in technology. This is an important approach to reduce unnecessary medical suffering due to undesired side effects that may result from the current one-size-fits-all approach. It will also help reduce treatment costs by eliminating ineffective treatment strategies. Since 1989, the death rate has been decreasing, primarily among women under the age of 50. These decreases are the result of increased awareness, highly sensitive diagnostic techniques, and treatment advancements. As of January 2019, 3.1 million women are alive, either undergoing treatment or having finished the treatment
In recent years, new biomarker-driven personalized agents have been approved by the FDA, namely, PARP inhibitors for HER2-negative disease (germline BRCA1/2-mutation-positive), Tecentriq for TNBC (PD-L1-positive), and Piqray for HR-positive/HER2-negative disease (PIK3CA mutation-positive). Further, data released at ASCO 2019 demonstrates the success of the latest personalized medicine strategy in breast cancer. The key studies evaluating personalized agents for HER2-positive breast cancer were presented, along with other interesting new data setsfor drugs targeting TNBC and HR-positive/HER2-negative disease. These studies are described below.
MONALEESA-7 trial: The most recent survival data from this randomized trial have been presented, in which 672 pre- or perimenopausal women with ER-positive/HER2-negative advanced breast cancer were treated with standard endocrine therapy (nonsteroidal aromatase inhibitor) and tamoxifen with or without ribociclib (CDK 4/6 inhibitor). At a median follow-up of 34.6 months, death risk was reduced by 29% in women being treated with ribociclib vs. endocrine therapy alone (p=0.00973; median OS: not reached vs. 40.9 months). The higher proportion of women was alive at 36 (71.9% vs. 64.9%) and 42 months (70.2% vs. 46%).
NALA trial: In this registration-randomized study, 621 women with third- and later-line HER2- positive metastatic breast cancer were treated with capecitabine vs. neratinib or capecitabine and lapatinib. This study also allowed the inclusion of women with asymptomatic and stable brain metastases. Progression-free survival (PFS), the primary endpoint, was prolonged with neratinib and capecitabine vs lapatinib and capecitabine (mean improvement by 2.2 months; p=0.0059). Overall survival, the co-primary endpoint, favored neratinib, but the improvement was not statistically significant. Fewer patients in the neratinib group required intervention for symptomatic central nervous system (CNS) metastases, pointing a delay in CNS progression. Patients in both groups experienced diarrhea as a frequently reported adverse effect, but grade 3 diarrhea was more frequent in the neratinib group (24% vs. 13%).
SOPHIA trial: This randomized study compared the efficacy of trastuzumab vs margetuximab in 536 patients (2nd to 4th line) with HER2-positive metastatic breast cancer. The median PFS was improved with margetuximab compared to trastuzumab (5.8 vs. 4.9 months; p=0.0333); clinical benefit rates and objective response were also superior with margetuximab. The PFS benefit with margetuximab was more in the subset of CD16A-158 genotype patients (6.9 months vs. 5.1 months). The OS was immature, and toxicity was similar between the arms.
aTTom trial: To predict the benefit of extending tamoxifen for patients with HR-positive breast cancer, this randomized phase III study involved nearly 7,000 patients with HR-positive breast cancer who had completed a minimum of four years of tamoxifen therapy. Patients were assigned to either continue or discontinue tamoxifen treatment for an additional five years. At the median follow-up of 12 years, BCI H/I was predictive of endocrine response in women with node-positive cancer: the 49% of these women identified as H/I high gained significant benefit from 10 versus 5 years of tamoxifen therapy (p=0.027), whereas the 51% classified as BCI H/I low gained no benefit from additional tamoxifen therapy. Tools such as BCI offer an opportunity to more granularly discriminate among patients with similar clinical features and tailor treatment recommendations accordingly.
A new era of personalized medicine has been heralded with the discovery of “omics” technologies. This new paradigm is beginning to affect both clinical practice and research, as well as the healthcare industry.
The use of personalized medicines is growing rapidly and having an impact on drug discovery, drug development, and patients’ diagnosis and treatment processes. As discussed, breast cancer is highly heterogeneous in nature; therefore, before treatment selection, one should thoroughly study the nature of the disease. By encouraging the development of personalized medicines for patients with breast cancer, maximum benefits can be provided to patients that have already been proven by the discovery of trastuzumab.
Reviewer: Manisha
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