Long-term radiotherapy reduces local breast cancer recurrence but not overall survival

28th November 2022

The longer-term use of radiotherapy has been shown to reduce local breast cancer tumour recurrence but does not affect overall survival

Use of radiotherapy for 30 years in patients following breast conserving surgery in conjunction with chemotherapy or tamoxifen, reduces the risk of ipsilateral breast tumour recurrence but does not affect overall survival, according to the findings of follow-up study presented at the European Breast Cancer Conference in November 2022.

For a lot of women with early-stage breast cancer, breast-conserving surgery removes macroscopic disease although the presence of any remaining microscopic tumour tissue, if left untreated, could lead to loco-regional recurrence or life-threatening distant metastases. As a result, adjuvant radiotherapy, is often used and the evidence from over 10,000 women, suggests that radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. In 1976, researchers began a randomised trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. Results after 6 years showed that the relapse rate in the ipsilateral breast was 24.5% in the non-irradiated group compared to 5.8% following breast irradiation. But the researchers continued to monitor patients and the results showed that after 20 years of follow-up, there were no significant differences in overall survival among women who underwent mastectomy and those who underwent lumpectomy with or without postoperative breast irradiation. However, the study did show that the cumulative incidence of recurrent tumour in the ipsilateral breast was 14.3% in the women who underwent breast irradiation, compared with 39.2% in the women without irradiation. In the present Now, researchers are able to present 30-year survival data.

Radiotherapy and overall survival following breast cancer surgery

A total of 585 patients aged ≤70 years with early breast cancer, underwent local excision with a 1 cm margin, axillary node sampling or axillary node clearance.

Overall, researchers observed that ipsilateral breast tumour recurrence was found to be significantly lower in the radiotherapy group (Hazard ratio, HR = 0.39, 95% CI 0.27 – 0.55). For example, local recurrence (LR) after 10 years was 8.8% vs 31% (radiotherapy vs non-irradiated) but this difference reduced after 30 years and was 27.8% (95% CI 19 – 36.5) in the irradiated group and 42.7% (95% CI 35.8 – 49.6) in the non-irradiated group.

Furthermore, there was no difference in overall survival after 30 years (HR = 1.08, 95% CI 0.89 – 1.30, p = 0.43) and the proportion of survivors was broadly similar over time. For instance, overall survival at 10 years was 72.5% vs 70.8% (irradiated vs non-irradiated) and this difference was broadly similar after 30 years (23.7% vs 27.5%).

In a press release from the conference, lead researcher, Professor Ian Kunkler said, ‘We found that there is no long-term improvement in overall survival for those women having radiotherapy‘. He added that ‘The benefits of having radiotherapy in terms of fewer local recurrences are only accrued over the first ten years after radiotherapy; thereafter, the rate of local recurrence is similar whether or not patients had radiotherapy.’

Citation
Williams L et al. Randomised controlled trial of breast conserving therapy: 30 year analysis of the Scottish breast conservation trial. Abstract No 2. 13th European Breast Cancer Conference.

Aspirin use in residual breast cancer disease improves distant metastases free survival 

28th October 2022

Aspirin use in breast cancer patients with residual disease after neoadjuvant chemotherapy led to improved distant metastases free survival

Aspirin use in women with breast cancer who were unable to achieve nodal clearance after neoadjuvant chemotherapy, significantly improved 5-year distant metastases free survival according to the findings of an analysis presented at the World Cancer Congress in Geneva, 2022 by researchers from University of Texas Southwestern, Dallas, US.

Breast cancer affects a huge number of women with data from the World Health Organisation suggesting that globally in 2020, there were 2.3 million diagnoses and 685 000 deaths. However, survival depends to a large extent on how far the disease has spread. For example, where localised, 5-year survival is 99% but if the disease has become more widespread, survival drops to 29%. Triple negative breast cancer is a particularly aggressive form of the disease such that if this form becomes metastatic, 5-year survival reduces to 12%. In a 2017 small study of 65 patients with triple negative breast cancer and stage II or III disease, researchers found that use of anti-platelet agents such as aspirin, led to significant improvements in 5-year disease-free survival and distant metastases rate. In addition, other work in patients with high-risk prostate cancer has also shown that aspirin use led to improved overall survival.

A pathological complete response (pCR) represents a state in which there is complete eradication of invasive carcinoma, for example, from breast and axillary lymph nodes as well as within blood or lymph vessels. This measure has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival and overall survival. In fact, one analysis suggests that breast cancer patients who achieve pCR after neoadjuvant chemotherapy had a 64% lower risk of death compared to those who had residual disease at the time of surgery.  Furthermore, a higher residual cancer burden disease is significantly associated with worse event-free survival. Nevertheless, whether aspirin use in patients with residual disease confers any benefits is uncertain and was examined in the present study.

Researchers retrospectively identified patients without a pCR and with residual node disease after neoadjuvant chemotherapy and focused on the effect among those prescribed aspirin. The outcomes of interest were overall survival (OS), disease-free survival (DFS) and distant metastases-free survival (DMFS) using Kaplan Meier analysis and logistic regression.

Aspirin use and survival outcomes

A total of 637 patients, 48 of whom with a median age of 48 years were using aspirin, were followed-up 3.7 years.

Disease free survival was significantly higher among those using aspirin (Hazard ratio, HR = 0.54, 95% CI 0.32 – 0.92, p = 0.024) although DMFS was non-significant (HR = 0.63, 95% CI 0.38 – 1.05, p = 0.07). In contrast, in multivariate analysis among those with residual disease, aspirin use was significantly associated with an improvement in DMFS (HR = 0.52, 95% CI 0.29 – 0.94, p = 0.031).

The authors concluded that among breast cancer patients who have residual disease following neoadjuvant chemotherapy, aspirin use appeared to be associated with a significant improvement in 5-year disease and distant metastases survival. They added that future research should consider augmented aspirin use in high-risk breast cancer patients who do not achieve pCR.

Citation
Johns C et al. Aspirin Use is Associated with Improvement in Distant Metastases Outcome in Patients with Residual Disease after Neoadjuvant Chemotherapy Number 2009 World Cancer Congress, 2022

Adjuvant metformin of no benefit in non-metastatic breast cancer

7th June 2022

Addition of metformin to standard chemotherapy for breast cancer did not produce a significant improvement of invasive disease-free survival

Adding metformin to standard breast cancer chemotherapy in women with non-metastatic, high-risk operable breast cancer, did not lead to a significant improvement of invasive disease-free survival. This was the conclusion of a randomised trial conducted by researchers in Canada, Switzerland and the UK.

Diabetic patients who develop cancer havea 40% higher mortality risk than non-diabetics. In addition, studies have suggested that type 2 diabetes may be associated with 10-20% excess relative risk of breast cancer.

The drug metformin is a biguanide that is used in the treatment of type 2 diabetes and works by decreasing gluconeogenesis and increases peripheral utilisation of glucose. In a 2015 meta-analysis of 11 studies, that compared the outcomes of breast cancer therapy in diabetes with and without metformin, the authors concluded that use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients.

However, this is not a consistent finding in the literature. For instance, another study of over 2,300 women with breast cancer, the authors concluded that their study failed to show an association between improved survival and increased cumulative metformin use in breast cancer patients who had recent-onset diabetes.

In contrast, a 2012 retrospective analysis, found that diabetic patients with breast cancer who received metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than those not receiving the drug.

However, the data in the above studies is derived from observational studies which are subject to several forms of bias. As a result, for the current study, the researchers focused specifically on metformin and undertook a randomised trial to determine whether the use of metformin in breast cancer patients without diabetes, positively impacted on treatment outcomes.

Adult women without diabetes who received standard therapy for a T1 to T3, No to N3, MO breast cancer were recruited and stratified as either oestrogen and/or progesterone receptor positive (ER/PgR +) or negative (ER/PgR -).

Enrolled participants were then randomised 1:1, to 850 mg of metformin once daily or matching placebo for 4 weeks. The dose was then increased to twice daily for 5 years. Patients were followed-up at 6 and 12 months and then annually.

The primary endpoint of the trial was invasive disease-free survival. Secondary outcomes included overall survival and the incidence rates for death.

Metformin and invasive disease-free survival

A total of 3649 women with a mean age of 52.4 years of whom, 2533 were ER/PgR + were recruited. However, futility was declared for the ER/PgR- group and so the analysis was restricted to the 2533 women who were ER/PgR +.

After a median follow-up of 96.2 months, 18.4% of women had invasive disease-free survival (234 in the metformin group vs 231 in the placebo arm), giving an incidence rate of 2.78 per 100 patient-years in the metformin group and 2.74 in the placebo group (hazard ratio, HR = 1.01, 95% CI 0.84 – 1.21, p = 0.93). Similarly, the risk of death was not significantly different (HR = 1.10, 95% CI 0.86 – 1.41, p = 0.47).

Although futility was declared for those with ER/PgR-, among the patients who were followed up for a median of 94.1 months, there was also no difference in the level of invasive disease-free survival (HR = 1.01, 95% CI 0.79 – 1.30, p = .082). There were also no significant differences in any of the secondary outcomes.

The authors concluded that despite the evidence from observational studies, use of adjunctive metformin did not improve invasive disease-free survival in women with breast cancer.

Citation
Goodwin PJ et al. Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial JAMA 2022

HRT use increases risk of disease recurrence in breast cancer survivors

18th November 2021

Meta-analysis shows HRT use among women who have survived breast cancer is associated with a significant increased risk of disease recurrence.

Hormone replacement therapy (HRT) use for the management of menopausal symptoms in women with a history of breast cancer is associated with a significant increase in the risk of disease recurrence according to a meta-analysis by researchers from Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy. Although there have been major advances in the treatment of breast cancer, the blocking of oestrogen is associated with several adverse effects which negatively impact on a patient’s quality of life. HRT use is the most effective treatment for symptoms related to a reduction in the level of oestrogen although its use in breast cancer survivors is generally avoided. Among healthy women, the use of oestrogen only HRT leads to a reduced risk of breast cancer but when oestrogen is combined medroxyprogesterone, the risk is increased. Though it is generally advised that the use of HRT is avoided in patients with a history of breast cancer it has been suggested that there is insufficient evidence to contra-indicate HRT in breast cancer survivors.

With some uncertainty over whether HRT increases the risk in breast cancer survivors who experience oestrogen depletion-related symptoms, the Italian team decided to perform a systematic review and meta-analysis to assess the overall safety of systemic HRT use and its impact on disease recurrence in breast cancer survivors. They searched all of the main databases but restricted their search to articles published in English, randomised, placebo-controlled trials with breast cancer survivors and any studies reporting on the recurrence of breast cancer.

Findings

The literature search identified 12 studies of which, only 4 were included in the final analysis examining the effect of HRT on 4050 breast cancer survivors. All trials had randomised patients to either HRT or placebo with a total of 2022 patients randomised to HRT, either oestrogen/progestogen combinations or tibolone.

There was a low degree of heterogeneity in studies and compared to the placebo group, the use of HRT significantly increased the risk of breast cancer recurrence (hazard ratio, HR = 1.46, 95% CI 1.12 – 1.91, p = 0.006). In subgroup analysis, among patients with hormone receptor-positive tumours, the risk of disease recurrence was also significantly increased in those using hormonal therapy (HR = 1.80, 95% CI 1.15 – 2.82, p = 0.010). In contrast, in patients with hormone receptor-negative disease, there was no significant increase in risk (HR = 1.19, 95% CI 0.80 – 1.77, p = 0.39). In a further analysis, the risk of breast cancer recurrence was no different between combined HRT and tibolone (HR = 1.51 95% CI 0.84 – 2.72).

Based on these findings, the authors concluded that future research should focus on finding alternatives to hormone replacement therapy for women who have survived breast cancer yet experience symptoms related to oestrogen deficiency.

Citation

Poggio F et al. Safety of systemic hormone replacement therapy in breast cancer survivors: a systematic review and meta-analysis. Breast Cancer Res Treat 2021