Comprehensive Geriatric Assessment for Older Women with Early-Stage (Non-Metastatic) Breast Cancer-An Updated Systematic Review of the Literature.

BACKGROUND: A previous systematic review by our team (2012) undertook comprehensive geriatric assessment (CGA) in breast cancer and concluded there was not sufficient evidence to instate CGA as mandatory practice. SIOG/EUSOMA guidelines published in 2021 advocate the use of CGA in breast cancer patients. The aim is to perform an updated systematic review of the literature. METHODS: A systematic review of studies published between 2012 and 2022 that assessed the use of CGA in breast cancer was performed on Cochrane, PubMed and Embase. RESULTS: A total of 18 articles including 4734 patients with breast cancer were identified. The studies covered four themes for use of CGA in breast cancer: (1) to determine factors influencing survival (2) as an adjunct to treatment decision-making (3) to measure quality of life, and (4) to determine which tools should be included. There was evidence to support the use of CGA in themes 1-3; however, it is uncertain which assessment tools are best to use (theme 4). CONCLUSIONS: CGA can be used to determine factors affecting survival and quality of life in breast cancer patients and can therefore be used to aid treatment decision-making. Further work is required to determine gold standard CGA.

Oncoplastic breast surgery in older women with primary breast cancer: systematic review.

BACKGROUND: Oncoplastic procedures allow excision of larger breast tumours, or unfavourable tumour/breast ratio lesions while achieving a good cosmetic outcome. This increases the pool of patients eligible for breast conservation over mastectomy, reducing the need for more extensive surgery in older women and potentially improving their quality of life. Nonetheless, studies to date suggest a poor uptake of oncoplastic breast surgery in the older group. This review aimed to establish whether a disparity in uptake of oncoplastic breast surgery exists between older and younger women, and to explore the underlying reasons for this. METHODS: A literature search was conducted on 17 January 2022 using MEDLINE and Embase. Eligible studies comprised full-text articles of patients who underwent oncoplastic breast surgery for primary invasive breast cancer, and included those aged at least 65 years. RESULTS: Ten published studies were identified. One study was ranked as providing level 2 evidence, and the remainder were level 3. A total of 567 women underwent oncoplastic breast surgery for primary breast cancer, of whom only 61 (10.8 per cent) were aged 65 years or older. None of the studies directly compared younger with older women, or explored the underlying factors contributing to this discrepancy in uptake. CONCLUSION: This review has demonstrated a lower uptake of oncoplastic breast surgery in older compared with younger women. Given the increasing number of older women living with breast cancer who may be eligible for breast-conserving surgery, further research into this area is required.

Assessment of the Androgen Receptor in Older Women with Primary Breast Cancer: Association with a Panel of Biomarkers and Breast Cancer Specific Survival.

INTRODUCTION: Breast cancer in older women tends to have more favourable biology, compared to younger women. Androgen receptor (AR) is significant for breast tumour carcinogenesis; however, the role of AR in older women has not been fully explored. METHODS: Surgical specimens were obtained from an existing series of 1758 older women (≥ 70 years) with primary breast cancer, treated in a single institution with long-term (≥ 37 years) follow-up. As part of previous work, it was possible to construct good quality tissue microarrays (TMAs) in 575 surgical specimens and a panel of 24 biomarkers was measured by immunohistochemistry (IHC) in these TMAs. AR positivity was assessed by IHC and defined as H-score ≥ 40. The relationship between AR in this cohort was compared to an equivalent group of younger women (< 70 years, n = 1708); the panel of 24 biomarkers and breast cancer specific survival (BCSS) in the older cohort. RESULTS: AR was assessed in 509 samples. Overall, 59% of the older women cohort had positive expression of AR, compared to 63% in the younger cohort. AR positivity (regardless of age) was associated with smaller size of tumour, lower grade of tumour, lower tubule formation, lower nuclear polymorphism and lower mitotic frequency. AR positivity was associated with positive expression of oestrogen receptor (ER), progesterone receptor (PR), breast cancer gene 1 (BRCA1), cytokeratin (CK) 7/8, CK18, CK19, B cell lymphoma (Bcl)2 and Mucin 1 (Muc1) expression. Conversely, AR-positive expression was associated with negative expression of human epidermal growth factor receptor 2 (HER2), Ki-67, CK5, CK17, epidermal growth factor receptor (EGFR), and CD44 expression. Older women with AR-positive tumours had better BCSS compared to AR-negative tumours (p = 0.009). CONCLUSIONS: There was no difference in AR expression between older and younger women with breast cancer. AR has prognostic potential in terms of BCSS. Further work is needed to investigate AR as a therapeutic target.

The Association Between Medication Use in Older Women with Early-Stage Operable Primary Breast Cancer and Decision Regarding Primary Treatment.

BACKGROUND: Polypharmacy is one factor contributing to increased mortality, hospitalization, and adverse drug reactions in older adults. The aim of this study was to measure the prevalence of polypharmacy in a cohort of older women with early-stage operable primary breast cancer and the relationship of polypharmacy to primary treatment decision and functional status. METHODS: A total of 139 patients with a new diagnosis of early-stage operable primary breast cancer proven histologically were recruited as part of a prospective study. The average age was 77 years. Assessment using a cancer-specific Comprehensive Geriatric Assessment (CGA) tool was conducted within 6 weeks of diagnosis of breast cancer. Association was determined between number of medications and treatment decision and physical status as measured by the CGA outcomes. Additional analysis was performed to determine the associations above with polypharmacy defined by ≥5 daily medications, and if cardiovascular-related diseases have a role in the treatment decision. RESULTS: Polypharmacy was present in 48% of patients (n = 139). CGA determined that polypharmacy was associated with greater comorbidity (P < .001), reduced physical status rated by physicians (P = .009) and patients (P = .019), and reduced ability to perform activities of instrumental ADLs (P = .008). Similar findings were present in the analysis of cardiovascular-related diseases. CONCLUSIONS: This work suggests that patients with polypharmacy are more likely to be frail. The number of medications could help us screen patients who should go on to receive full CGA.

Molecular Biomarker Expression in Window of Opportunity Studies for Oestrogen Receptor Positive Breast Cancer-A Systematic Review of the Literature.

Window of opportunity (WoO) trials create the opportunity to demonstrate pharmacodynamic parameters of a drug in vivo and have increasing use in breast cancer research. Most breast cancer tumours are oestrogen receptor-positive (ER+), leading to the development of multiple treatment options tailored towards this particular tumour subtype. The aim of this literature review is to review WoO trials pertaining to the pharmacodynamic activity of drugs available for use in ER+ breast cancer in order to help guide treatment for patients receiving neoadjuvant and primary endocrine therapy. Five databases (EMBASE, Cochrane, MEDLINE, PubMed, Web of Science) were searched for eligible studies. Studies performed in treatment-naïve patients with histologically confirmed ER+ breast cancer were included if they acquired pre- and post-treatment biopsies, compared measurement of a proteomic biomarker between these two biopsies and delivered treatment for a maximum mean duration of 31 days. Fifteen studies were eligible for inclusion and covered six different drug classes: three endocrine therapies (ETs) including aromatase inhibitors (AIs), selective oestrogen receptor modulators (SERMs), selective oestrogen receptor degraders (SERDs) and three non-ETs including mTOR inhibitors, AKT inhibitors and synthetic oestrogens. Ki67 was the most frequently measured marker, appearing in all studies. Progesterone receptor (PR) and ER were the next most frequently measured markers, appearing five and four studies, respectively. All three of these markers were significantly downregulated in both AIs and SERDs; Ki67 alone was downregulated in SERMs. Less commonly assessed markers including pS6, pGSH3B, FSH and IGF1 were downregulated while CD34, pAKT and SHBG were significantly upregulated. There were no significant changes in the other biomarkers measured such as phosphate and tensin homolog (PTEN), Bax and Bcl-2.WoO studies have been widely utilised within the ER+ breast cancer subtype, demonstrating their worth in pharmacodynamic research. However, research remains focused upon routinely measured biomarkers such ER PR and Ki67, with an array of less common markers sporadically used.

Immediate breast reconstruction uptake in older women with primary breast cancer: systematic review.

BACKGROUND: Postmastectomy immediate breast reconstruction (PMIBR) may improve the quality of life of patients with breast cancer, of whom older women (aged 65 years or more) are a growing proportion. This study aimed to assess PMIBR in older women with regard to underlying impediments (if any). METHODS: MEDLINE, Embase, and PubMed were searched by two independent researchers up to June 2022. Eligible studies compared PMIBR rates between younger and older women with invasive primary breast cancer. RESULTS: A total of 10 studies (2012-2020) including 466 134 women were appraised, of whom two-thirds (313 298) were younger and one-third (152 836) older. Only 10.0 per cent of older women underwent PMIBR in contrast to 45.0 per cent of younger women. Two studies explored factors affecting uptake of PMIBR in older women; surgeon-associated (usual practice), patient-associated (socioeconomic status, ethnicity, and co-morbidities), and system-associated (insurance status and hospital location) factors were identified. CONCLUSION: Uptake of PMIBR in older women is low with definable (and some correctable) barriers.

Concordance between core needle biopsy and surgical excision specimens for Ki-67 in breast cancer - a systematic review of the literature.

AIMS: The biomarkers oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are routinely measured in patients with breast cancer with international consensus on how they should be interpreted. There is evidence to support use of other biomarkers to give more detailed predictive and prognostic information. Ki-67 is one example, and measures the proliferative activity of cancer cells. It is important that this can be performed at diagnosis of breast cancer for patients who do not have initial surgical treatment (mainly older women) and those receiving neoadjuvant therapies. METHODS AND RESULTS: A systematic review was performed to assess concordance of measurement of Ki-67 between core needle biopsy (CNB) samples and surgical excision (SE) samples in patients with invasive breast cancer. MEDLINE and Embase databases were searched. Studies were eligible if performed within the last 10 years; included quantitative measurement of Ki-67 in both CNB and SE samples with no prior breast cancer treatment; measured concordance between two samples; and had full text available. A total of 22 studies, including 5982 paired CNB and SE samples on which Ki-67 was measured, were appraised. Overall, there appeared to be concordance; however, reliability was unclear. Where given, the Cohen's kappa coefficient (κ) of correlation between samples ranged from 0.261 to 0.712. The concordance rate between CNB and SE where measured as a percentage had a range from 70.3 to 92.7% CONCLUSIONS: Assessment of level of concordance of Ki-67 between CNB and SE samples is hampered by different methodologies. International consensus on Ki-67 measurement is urgently needed.

Does Breast Cancer Surgery Impact Functional Status and Independence in Older Patients? A Narrative Review.

Surgery is the recommended treatment modality for primary breast cancer. Breast cancer surgery is non-visceral; therefore, it is often assumed that the subsequent impact on functional status in older women is less significant compared to other cancer types such as colorectal cancer. Evidence for this however, is lacking. The definition of functional status varies amongst healthcare professionals and patients, making comparisons between studies difficult. From the literature, the two most common themes in relation to functional status following breast cancer surgery are activities of daily living and quality of life. Both of these elements of functional status are adversely impacted in patients following breast cancer surgery. A more significant decline is seen in patients with pre-existing comorbidities and with greater intensity of surgery, which includes more invasive breast and/or axillary surgery as well as additional reconstructive procedures. Identifying and optimising pre-existing factors which may predict post-operative decline in functional status, such as cognitive impairment and deteriorating functional decline over the preceding year, may help in reducing deterioration in functional status after breast cancer surgery. Methods which may be employed to detect and optimise these factors include geriatric assessment and exercise intervention.

Current Challenges Faced by Cancer Clinical Trials in Addressing the Problem of Under-Representation of Older Adults: A Narrative Review.

The number of older adults living with cancer is increasing. There is a clear lack of representation of older adults in clinical trials, including cancer trials. Reasons for this are multifactorial and complex and include protocol, patient and sponsor factors. Potential solutions to overcome issues with trial design include varied methods of recruitment with flexible inclusion criteria. Possible alternatives to randomised trials include prospective cohort studies, pragmatic trials and the use of national population-based data sets. Patient factors may be addressed by integration of geriatric assessment, so patients can be randomised or treated based on their individual needs. Additionally, standard protocols for including older adults with cognitive impairment should be developed, rather than automatic exclusion. Increased effort is needed from sponsors and governing health care bodies to make recruitment of older adults to clinical trials standard.

Outcomes of removal of peritoneal dialysis catheter at the time of renal transplant.

There is no consensus regarding timing of peritoneal dialysis (PD) catheter removal following kidney transplant. We hypothesize that early removal of PD catheter reduces the risk of peritonitis. We conducted a prospective closed-loop audit to review existing practice in our department and determine whether a better strategy could be implemented. Simple descriptive and inferential statistics were used to generate results. Categorical data were described using frequency and percentage. Continuous values were reported as mean ± standard deviation. Between November 2016 and April 2017, forty patients had renal transplant with PD in situ. On average time to removal of PD catheter, posttransplant was 84 days. Four patients (10%) developed exit-site infection. Following departmental consultation, practice was changed to remove all PD catheters at the time of transplant. Between May 2017 and January 2018, twenty patients had renal transplant and 19 had PD catheter removed at the time of transplant. Of these, one required re-insertion. In the patient where PD catheter was left in situ, peritonitis was a complication. We continue to recommend PD catheter removal at the time of transplant.

The Potential Use of Tumour-Based Prognostic and Predictive Tools in Older Women with Primary Breast Cancer: A Narrative Review.

A move is under way towards personalised cancer treatment, where tumour biology of an individual patient is examined to give unique predictive and prognostic information. This is extremely important in the setting of older women, who have treatment-specific goals which may differ from their younger counterparts, and may include conservation of quality of life rather than curative intent of treatment. One method employed to assist with this is the use of tumour-based prognostic and predictive tools. This article explores six of the most common tumour-based tools currently available on the market: MammaPrint, Oncotype DX, Mammostrat, Prosigna, EndoPredict, IHC4. The article discusses the creation and validation of these tools, their use and validation in older women, and future directions in the field. With the exception of Oncotype Dx, which has also been licensed for prediction of response from adjuvant chemotherapy, these tools have been licensed for use as prognostic tools only, mainly in the setting of adjuvant therapy following surgery. The evidence base for use in older women is strongest for Mammostrat and PAM50, although overall the evidence is much weaker than that in younger women. Where older women have been included in validation studies, this is often in small numbers, or the exact proportion of older women is unknown. In practice, all six of the tools are recommended to be utilised on surgical excision specimens, as well as in core needle biopsy (CNB) specimens in all of the tools except Mammostrat. This is extremely important in the setting of older women, of whom a large proportion do not undergo surgery. The suggested nature of the sample is formalin-fixed paraffin-embedded in all the tools except MammaPrint, which can also be performed on fresh-frozen samples. Future development of prognostic tools in older women with breast cancer should focus on treatment dilemmas specific to this population. This includes the decision of primary treatment between surgery or endocrine therapy and decisions regarding adjuvant therapy, in particular, chemotherapy.

Invasive Lobular Breast Cancer as a Distinct Disease: Implications for Therapeutic Strategy.

Invasive lobular carcinoma comprises 10-15% of all breast cancers and is increasingly recognised as a distinct and understudied disease compared with the predominant histological subtype, invasive ductal carcinoma. Hallmarks of invasive lobular carcinoma include E-cadherin loss, leading to discohesive morphology with cells proliferating in single-file strands and oestrogen receptor positivity, with favourable response to endocrine therapy. This review summarises the distinct histological and molecular features of invasive lobular carcinoma with focus on diagnostic challenges and the impact on surgical management and medical therapy. Emphasis is placed on recent advances in our understanding of the unique molecular biology of lobular breast cancer and how this is optimising our therapy approach in the clinic.

Biology of Oestrogen-Receptor Positive Primary Breast Cancer in Older Women with Utilisation of Core Needle Biopsy Samples and Correlation with Clinical Outcome.

The majority of biological profiling studies use surgical excision (SE) samples, excluding patients receiving nonsurgical and neoadjuvant therapy. We propose using core needle biopsy (CNB) for biological profiling in older women. Over 37 years (1973-2010), 1 758 older (≥70 years) women with operable primary breast cancer attended a dedicated clinic. Of these, 693 had sufficient quality CNB to construct tissue microarray (TMA). The pattern of biomarkers was analysed in oestrogen receptor (ER)-positive cases, using immunohistochemistry and partitional clustering analysis. The biomarkers measured were: progesterone receptor (PgR), Ki67, Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor (HER)-2, HER3, HER4, p53, cytokeratins CK5/6 and CK7/8, Mucin (MUC)1, liver kinase B1 (LKB1), Breast Cancer Associated gene (BRCA) 1, B-Cell Lymphoma (BCL)-2, phosphate and tensin homolog (PTEN), vascular endothelial growth factor (VEGF), and Amplified in breast cancer 1 (AIB1). CNB TMA construction was possible in 536 ER-positive cases. Multivariate analysis showed progesterone receptor (PgR) (p = 0.015), Ki67 (p = 0.001), and mucin (MUC)1 (p = 0.033) as independent predictors for breast-cancer-specific survival (BCSS). Cluster analysis revealed three biological clusters, which were consistent with luminal A, luminal B, and low-ER luminal. The low-ER luminal cluster had lower BCSS compared to luminal A and B. The presence of the low-ER luminal cluster unique to older women, identified in a previous study in SE TMAs in the same cohort, is confirmed. This present study is novel in its use of core needle biopsy tissue microarrays to profile the biology of breast cancer in older women.

Cytoplasmic Cyclin E Is an Independent Marker of Aggressive Tumor Biology and Breast Cancer-Specific Mortality in Women over 70 Years of Age.

Multi-cohort analysis demonstrated that cytoplasmic cyclin E expression in primary breast tumors predicts aggressive disease. However, compared to their younger counterparts, older patients have favorable tumor biology and are less likely to die of breast cancer. Biomarkers therefore require interpretation in this specific context. Here, we assess data on cytoplasmic cyclin E from a UK cohort of older women alongside a panel of >20 biomarkers. Between 1973 and 2010, 813 women ≥70 years of age underwent initial surgery for early breast cancer, from which a tissue microarray was constructed (n = 517). Biomarker expression was assessed by immunohistochemistry. Multivariate analysis of breast cancer-specific survival was performed using Cox's proportional hazards. We found that cytoplasmic cyclin E was the only biological factor independently predictive of breast cancer-specific survival in this cohort of older women (hazard ratio (HR) = 6.23, 95% confidence interval (CI) = 1.93-20.14; p = 0.002). At ten years, 42% of older patients with cytoplasmic cyclin E-positive tumors had died of breast cancer versus 8% of negative cases (p < 0.0005). We conclude that cytoplasmic cyclin E is an exquisite marker of aggressive tumor biology in older women. Patients with cytoplasmic cyclin E-negative tumors are unlikely to die of breast cancer. These data have the potential to influence treatment strategy in older patients.

Personalising Care in the Older Woman with Primary Breast Cancer.

The incidence of breast cancer increases with age. Despite this, most research in the field is targeted at younger patients. Age-specific guidelines are not widely referred to and guidelines which allude to the older woman as an individual are based solely on conventional factors. This creates a problem for older women with primary operable breast cancer who are not fit, too frail or do not wish to have surgery. Preliminary studies have shown that older women with breast cancer have distinct biological features compared to their younger counterparts. This means that they are likely to have less aggressive cancers such as those who are oestrogen receptor-positive. Geriatric assessment (GA) has been used in clinical practice to identify patients that are suitable for certain treatments. More research on this group of patients' unique biological features and GA will help tailor personalised care for them.

Fulvestrant for the treatment of advanced breast cancer.

INTRODUCTION: The current issues with endocrine therapy for treatment of advanced breast cancer include balance of efficacy of therapy versus tolerability as well as hormone resistance. The efficacy of fulvestrant, a selective oestrogen receptor degrader (SERD), has been demonstrated in hormone receptor positive patients previously untreated or treated with hormonal therapy. Areas covered: This article discusses the journey of fulvestrant licensing, its efficacy in combination with other endocrine therapies and the future role it may have within breast cancer treatment. Expert commentary: Within phase III trials, fulvestrant has demonstrated equivalent or improved clinical efficacy when compared with established endocrine agents. In the recent decade, fulvestrant has achieved licensing as a second line agent in non-operative advanced breast cancer at initially 250mg, increasing to 500mg. Presently, fulvestrant is licensed globally as first line endocrine management for advanced breast cancer in post-menopausal women. Early combination trials of fulvestrant and cyclin dependent kinase 4/6 inhibitors have demonstrated good clinical efficacy with improved progression free survival when compared to fulvestrant alone.

Is Hydronephrosis a Complication after Anterior Lumbar Surgery?

Study Design Prospective follow-up design. Objective Ureteral injury is a recognized complication following gynecologic surgery and can result in hydronephrosis. Anterior lumbar surgery includes procedures like anterior lumbar interbody fusion (ALIF) and total disk replacement (TDR). Anterior approaches to the spine require mobilization of the great vessels and visceral organs. The vascular supply to the ureter arising from the iliac arteries may be compromised during midline retraction of the ureter, which could theoretically lead to ureter ischemia and stricture with subsequent hydronephrosis formation. Methods Potential candidates with previous ALIF or TDR via anterior retroperitoneal access between January 2008 and March 2012 were chosen from those operated on by a single surgeon in a university hospital setting (n = 85). Renal ultrasound evaluation of hydronephrosis was performed on all participants. Simple descriptive and inferential statistics were used to generate results. Results A total of 37 voluntary participants were recruited (23 male, 14 female subjects; average age 51.8 years). The prevalence of hydronephrosis in our population was 0.0% (95% confidence interval 0 to 8.1%). Conclusions Retraction of the ureter across the midline in ALIF and TDR does not result in an increase in hydronephrosis and appears to be a safe surgical technique.

The potential value of comprehensive geriatric assessment in evaluating older women with primary operable breast cancer undergoing surgery or non-operative treatment--a pilot study.

OBJECTIVES: Breast cancer in older women raises a number of discrete issues, including how healthcare professionals can best decide which patients are candidates for surgery. A pilot study involving women aged ≥70years newly diagnosed with early operable primary breast cancer was conducted aiming to explore the potential value of comprehensive geriatric assessment (CGA). MATERIALS AND METHODS: Decision of primary treatment followed consultation with the clinical team and was not guided by any aspect of this study. CGA, using a validated cancer-specific tool, was conducted within 6weeks and 6months after diagnosis, complemented by formal measures of quality of life (QOL) (using EORTC QLQ-C30 and QLQ-BR23) and semi-structured interviews. A total of 47 female patients with a new diagnosis of clinically early (stage 1 or 2; cT0-2N0-1M0) operable primary breast cancer proven histologically, were recruited. RESULTS: CGA determined that increasing age (≥80years) (p=0.001), greater (≥4) comorbidity (p=0.022), greater number (≥4) of daily medications (p=0.002), and slower (≥19s) timed up and go (TUG) (p=0.016) score were significantly related to non-surgical treatment at 6weeks after diagnosis. Baseline QOL scores were generally good and they remained stable at 6months follow-up. As opposed to CGA, there was no correlation between QOL scores and the treatment modality identified. Semi-structured interviews identified themes consistent with findings from QOL assessment. CONCLUSION: The pilot study confirmed the feasibility of conducting CGA in a research setting which appeared to have value in assessing this patient population. More data will be required to definitively identify the components for geriatric assessment in this setting. The study has now extended into two more centres.

Management of operable primary breast cancer in older women.

A considerable number of breast cancer diagnoses are made in older women. Differing physiological needs of older patients and biology of tumors compared with younger patients may alter treatment options between surgery and nonsurgical primary approaches. Adjuvant therapies may benefit these patients; however, concerns about toxicity and physical demands of treatment may affect patient choice regarding treatment. Furthermore, quality of life may be more important to the older individual than curative treatment alone. Growing evidence is emerging for employing Comprehensive Geriatric Assessment to determine other factors that may contribute to treatment decision-making in the older population. The way geriatric oncology is delivered varies, bringing the importance of the multidisciplinary team to the forefront of care delivery in this age group. Future research in this area should include combined consideration of tumor biology and geriatric needs.