Introduction

Breast cancer is the most common non-skin cancer in Australia, affecting 1 in 7 women by the age of 85 [1]. The Australian 2021 projected incidence of breast cancer in the older population, defined as 70 years or greater, is over 6300 [2]. This is more than a third of the entire projected incidence of approximately 20,000; mirroring international data that 30% of new breast cancer diagnosis occurs in older patients [3,4]. In Australia, the average life expectancy was 83.5 years in 2020 - A girl born in 2021, has an almost 40% chance to live to 100. Our older breast cancer (OBC) patients are living longer, and their management needs to be thoroughly considered. Given the variability in their health statuses, older patients are under-represented in clinical trials. This only leads to further difficulties with treatment decision-making due to the lack of appropriate evidence.

The Choosing Wisely guidelines, released by the Society of Surgical Oncology proposed cessation of routine sentinel lymph node biopsy (SLNB) in early-stage hormone receptor positive (HR+) OBC patients in 2016 [5]. The recent updated recommendations for OBC management proposed by the European Society of Breast Cancer Specialists and the International Society of Geriatric Oncology should be commended [6]. They highlighted the under-representation of these older patients in clinical trials and discussed the competing mortality risks complicating patient care. However, the recent recommendation of sentinel lymph node biopsy (SLNB) omission in cT1N0 luminal-A like tumours (Level IV evidence) does raise some concern.

Prior to determining whether we should offer or withhold a treatment, we should ensure that we have thoroughly evaluated OBC patients and their tumour biology. Studies in younger cohorts have shown symptomatic breast cancer patients have a more hostile tumour biology, relative to screen-detected breast cancers [7,8]. The tumours are typically of a higher grade and have greater rates of lymphovascular invasion (LVI) and nodal positivity – reflecting higher locoregional recurrence rates and negatively influencing patient prognosis [9-13]. Our hypothesis is that symptomatic OBC patients also have a more aggressive

tumour biology than screen-detected patients and subsequently we analysed the tumour biology and nodal involvement rates in T1 HR+ OBC patients in Australia, comparing screen-detected to symptomatic patients.

Patients and Methods

The BreastSurgANZ Quality Audit (BQA) was reviewed to identify all older patients (aged ≥ 70 years) diagnosed with T1N0M0 HR+ breast cancers from 1^s January 2001 to 31^st December 2019. Hormone receptor positivity (HR+) was defined as estrogen and progesterone receptor positive (ER/PR+), HER2 negative (Ki67% is not recorded). All patients underwent breast surgery and SLNB (± axillary clearance - as per institutional preference). Prospectively collected data were retrospectively reviewed. Breast cancer characteristics were reviewed based on the 7^th American Joint Committee on Cancer (AJCC) staging [14]. Male patients and those with incompletely recorded data were excluded from the study. Comparison was made between screen-detected breast cancer patients (Group A) and symptomatic patients (Group B).

Continuous variables were expressed as means and standard deviations and analyzed using the independent student T-test where the data followed a normal distribution. Data which did not follow a normal distribution, were reported as median and range and were analyzed using the Mann-Whitney U test. Categorical data were presented as counts and percentages and analyzed using the Chi-square test. Statistical analysis was performed using Stata (Version 14; College Station, TX).

Results

From 1 January 2001 to 31 December 2019, 11,746 patients were appropriately reported in the BQA. There were 4,841 (41.21%) screen-detected patients, Group A, and 6,905 (58.79%) symptomatic presentations, Group B (Table 1). The median age of patients differed between the two groups; Group A patients were on average younger, 73 years, compared to Group B patients, 77 years. (p < 0.001).

Tumour type distribution was similar for rates of IDC, ILC and other invasive mixed types. It was noted that tubular neoplasms were statistically more common in screen detected patients (3.3% versus 1.8%), whereas mucinous was more common for symptomatic (5% versus 3.7%). Key differences were noted regarding rates of histological grade and LVI – in keeping with the hypothesis that symptomatic patients had more aggressive biology. Histological grade was statistically higher for symptomatic patients compared to screen-detected cancer (p < 0.001); Grade 2 and 3 cancers comprised 69.9% of symptomatic cases, compared to only 60.4% in screen detected. LVI was also elevated in symptomatic patients compared to screen detected (16.5% versus 9.2%, p < 0.001).

Rates of SLNB were statistically higher in screen detected patients compared to symptomatic patients (94.6% versus 85.8%, p < 0.001). Conversely, the rate of nodal positivity was statistically higher in symptomatic patients compared to screen detected (22.2% versus 13.2%). Rates of N1-3 stages were all statistically higher in symptomatic patient (p < 0.001). It was noted that the median nodal harvest was comparable between the two groups (p = 0.151) Table 1.

Discussion

Our results have shown statistically significant differences between symptomatic and screen-detected cancers. This mirrors the current literature in the younger breast cancer cohort. It is well known that a larger tumour correlates with a higher likelihood of recurrence and lower survival. Early detection therefore provides a better chance of a successful treatment – this is the incentive behind the current BreastScreen Australia programme. Though smaller HR+ tumours have a far greater prognosis, there are tumour characteristics that influence prognostication. These include histological grade, LVI and nodal involvement; all of which are statistically elevated in symptomatic breast cancers, when compared to screen.

Histological tumour grade is related to the degree of tumour tissue differentiation and is calculated by the Nottingham Grading System (NGS). The NGS is recommended by multiple international bodies and is derived from the evaluation of three morphological features - nuclear pleomorphism, mitotic count and degree of tubule or gland formation [15]. The prognostic impact of histological grade has been well studied, with evidence that grade is as important a prognostic factor as lymph node stage [13,16]. It is no surprise that the 8^th edition of the AJCC has now included histological grade, impacting upon a patients defined stage of breast cancer [17]. Histological grade has been shown to provide significant prognostic information on chemotherapy benefit as well as patterns of survival, including BCSS, DFS and OS [16,18]. Stage II Grade 1 cancers have been shown to have a < 10% event risk at 10 years; however, Stage II Grade 2 or 3 cancers have a > 10% risk of event in 5-10 years [19]. Grade 3 cancers are more likely to recur, with metastasis occurring within 8 years [16].

Our study has shown that symptomatic patients have a statistically higher rate of histological Grade 3 breast cancers, compared to those that were screen detected. Approximately 70% of symptomatic patients present with either Grade 2 or 3 cancers, a far less favourable tumour biology than Grade 1. It is important to also consider the concordance of core needle biopsy and the excisional specimen is only moderate [20]. The inclination is towards underestimating the grade, particularly due to lower mitotic count estimates with quoted rates of 26-32.3% [21,22]. By considering the mode of detection, the subsequent surgical management may be impacted. A grade 1-2 T1 HR+ cancer on core biopsy may be considered for SLNB avoidance. If this was symptomatically detected, the likelihood that the grade would be higher on final histopathology increases and subsequently, SLNB management should change.

LVI is defined as the presence of malignant tumour cells in lymphatic or blood vessels and has been shown to be suggestive of a highly proliferative cancer [23]. As an independent factor, LVI negatively impacts local recurrence rates, distant relapse, and overall survival [24,25]. Recent studies have also drawn attention to LVI’s impact on survival after neoadjuvant chemotherapy - a potential prognosticator superior to pathological complete response [26-28]. In our study, the presence of LVI was statistically higher in symptomatic patients; positive in over 50% more cases. This is another indicator that symptomatic patients have a different tumour biology when compared to screen-detected tumours. Though grade can be commented on a core biopsy, LVI is diagnosed on the excisional specimen only. It is thus highly important to be aware that modality of cancer detection influences the risk of LVI.

The Choosing Wisely recommendation references 4 studies only [29-32]. Only 3 of the 4 papers referenced are studies directly evaluating axillary surgery. The Cancer and Leukemia Group B (CALGB) 9343 trial evaluated the addition of radiotherapy (RT) to Tamoxifen for early stage OBC. Though it did not identify any survival improvement, they identified a statistically significant absolute reduction in 10-year loco regional recurrence of 8%. Rudenstam, et al. randomly assigned axillary dissection to node negative patients, with cohort sizes in the 200s. In this randomised control trial, there were 6 axillary recurrences in the untreated axilla cohort, compared to 2 recurrences in the Axillary Lymph Node Dissection (ALND) arm, with the questionable determination of no statistical significance. The study by Chung et al. was a retrospective review of only 140 patients, with a median follow up of less than 5 years. There was 1 axillary recurrence and 4 breast cancer related deaths within the cohort. Martelli, et al. compared ALND impact for cN0 OBC patients. After a median of 15 years breast cancer mortality was comparable. In the non-ALND group, 30 of 499 had ipsilateral axillary disease, of which 50% of these went on to develop distant metastases and subsequent death. The consideration to significantly change management, without Level I evidence, challenges our fundamental approach of evidence-based medicine.

There are many that have questioned the appropriateness of the Choosing Wisely stance [33-36]. SLNB is a minimally invasive procedure with very low risks. Its’ results can alter patient adjuvant management; directing whether radiotherapy, endocrine therapy and/or chemotherapy may be offered [37-39]. The decision to minimise unnecessary surgical intervention is sensible if it will not impact patient management, or if overall life expectancy is short. Studies are reporting no improvement in LRFS, DFS or OS with the omission of SLNB or RT however follow up is limited to 4-5 years only [38,39]. Subsequently, if the results of the SLNB would impact management, we would still recommend performing a SLNB in all cT1N0 symptomatic OBC patients.

Conclusion

The current international stance is de-escalating treatment of breast cancer in selected older patients. It is understandable to recommend a reduction in an intervention when the time to impact is greater than the patient’s survival. However, we have shown that not all T1 HR+ OBC patients are equal, and it is pivotal to ensure we are not providing sub-standard care for patients. Though the patients may be classified as older, their longevity is also increasing. For patients who can survive another 2-3 decades, the subsequent impact of withholding treatment options is inappropriate.

There are significant risk differences in OBC patients - commencing with their means of diagnosis. We have shown that symptomatic patients have statistically significant different tumour biology compared to screen-detected patients and their higher rate of nodal involvement needs to be considered. The risk-benefit-ratio is low - SLNB has minimal morbidity, yet the information derived can grossly impact adjuvant therapy recommendations. These differences should be further assessed – and mode of diagnosis should be strongly considered prior to determining de-escalation of OBC management. At this stage, we propose that all healthy, symptomatic cT1N0 HR+ OBC patients should still be offered SLNB until further studies are attended.

Weakness

An obvious shortcoming of our study is the inability to review recurrence and overall survival. There is significant literature available reporting these rates, as discussed above. The BQA is a surgeon-reported audit, thus the onus of updating patient recurrence and mortality is on the surgeon. Fortunately for patients, mortality from breast cancer in Australia is low; from a database perspective however, this results in an inability to update patient mortality from other causes. In Australia, a patient’s death in a hospital or nursing home, are reported to their general practitioner, not to their affiliated surgeon. Therefore, a proposed direction for the BQA would be the incorporation of the National Death Index (NDI), a Commonwealth database recording deaths and their causes.

Tables

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