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Women who take vitamin D after being diagnosed with breast cancer may have an increased chance of survival, new research supported by the Irish Cancer Society has shown.
Researchers from the Irish Cancer Society cancer research centre BREAST-PREDICT analysed data from almost 5,500 breast cancer patients and found that taking vitamin D supplements after diagnosis was associated with an increased relative survival of 20 per cent compared to those who did not.
For the research, recently published in the journal Breast Cancer Research and Treatment, anonymised data on the pharmacy claims of women with a record of invasive breast cancer aged 50-80 years between 2000 and 2011 (n = 5417) was provided by the National Cancer Registry of Ireland.
Initiation of de novo vitamin D post-diagnosis was identified from linked national prescription data (n = 2581, 49 per cent). Multivariate Cox proportional hazards models were used to estimate adjusted HRs (95 per cent CIs) for breast cancer-specific mortality.
There was a 20 per cent reduction in breast cancer-specific mortality in de novo vitamin D users (modelled as a time-varying variable) compared to non-users (HR 0.80; 95 per cent CI 0.64–0.99, p = 0.048) and the reduction was greater at 49 per cent (HR 0.51; 95 per cent CI 0.34–0.74, p < 0.001), if vitamin D was initiated soon after the breast cancer diagnosis (within six months).
Vitamin D, therefore, has the potential as a non-toxic and inexpensive agent to improve survival in breast cancer patients, the study authors concluded, adding there is a need for RCTs exploring the effect of vitamin D supplementation on breast cancer survival.
This research was led by RCSI researcher Dr Jamie Madden, under the supervision of Prof Kathleen Bennett, Associate Professor in Pharmacoepidemiology at RCSI Dublin.
“Previous studies have found that higher blood levels of vitamin D, which can come from our diet, sunlight or supplements, is associated with increased breast cancer survival. Our study suggests that vitamin D supplementation might be useful for women diagnosed with breast cancer. Large clinical trials are already underway overseas to look into this further,” Prof Bennett said.
While the findings are significant, the researchers did not have access to information on other measures from the women that could possibly impact their likelihood of better outcome. For example, increasingly studies are showing that moderate physical activity and maintaining a healthy diet can benefit a patient undergoing cancer treatment but this was not collected in this study.
The research also found vitamin D users to be younger on average, be less likely to smoke and have lower tumour stage and tumour grade progression compared to non-users, all factors more likely to be associated with better survival.
Dr O’Connor added: “Before rushing out to buy vitamin D supplements, we urge women with breast cancer to first talk to their medical team. Vitamin D use can cause health issues and each woman’s cancer is unique and will require personalised treatment.
“While this is an important preliminary study, the findings only shows an association, and not causal link. We will only know if vitamin D supplementation should be recommended to improve breast cancer treatment outcome in the coming years when the results of clinical trials emerge.”
A separate study carried out by BREAST-PREDICT researchers is focusing on the development of a personalised therapeutic strategy for HER2-positive breast cancer patients with ERBB gene mutations.
At least one-in-five HER2-positive breast cancer patients have cancers that are resistant or become resistant to the latest targeted therapies.
This study used tumour samples from 227 Irish HER2-positive breast cancer patients and found that 7 per cent of patients had mutations in these genes. Mutations were most common in the ERBB4 gene. The researchers then tested cell lines with and without these mutations with different anti-cancer drugs to see if the mutations would make the cells grow more aggressively or make them less likely to respond to the drugs.
One of the mutations that was tested (ERBB4-V721I) made the cells grow more aggressively. Cells with this mutation were less likely to respond to afatinib, an EGFR tyrosine kinase inhibitor, which targets the ERBB family. However, the cells were more likely to respond to the newer phosphoinositide 3-kinase (PI3K) inhibitor copanlisib.
According to study co-author Dr Sinead Toomey, “Although our findings need to be confirmed in a larger study, it is possible that these mutations may be able to tell us which patients will respond or not respond to certain therapies, and ultimately we hope to be able to use this information to personalise treatment so as to increase the percentage of women with HER2-positive breast cancer who we are able to treat effectively.”
Commenting on BREAST-PREDICT’s work to date, Head of Research at the Irish Cancer Society, Dr Robert O’Connor, said: “Since the Irish Cancer Society established BREAST-PREDICT five years ago, we’ve funded the work of over 50 breast cancer researchers across the country. That’s meant a €7.5 million investment that’s only been possible through the public’s generous donations.
Cancer Trials Ireland is currently involved in a number of breast cancer trials, at various stages of initiation and completion. See tinted panel below for information on its trials that are investigating overcoming HER2-therapy resistance in breast cancer.
Cancer Trials Ireland sponsored trials investigate overcoming HER2-therapy resistance in breast cancer
Dr Anees Hassan, Beaumont Hospital, Dublin; Dr Niamh M Keegan, RCSI Molecular Medicine; Andrés Hernando, MSc, Senior Clinical Project Manager, Cancer Trials Ireland; and Prof Bryan T Hennessy, Clinical Lead, Cancer Trials Ireland, RCSI Molecular Medicine, and Consultant Medical Oncologist, Beaumont Hospital
Sponsored by Cancer Trials Ireland, the PantHER (CTRIAL-IE 15-02) and Panthera (CTRIAL-IE 17-13) trials is assessing the addition of copanlisib to HER2-targeted agents to overcome HER2-therapy resistance in breast cancer.
Breast cancer (BC) is the second most common cancer and the fifth cause of cancer mortality worldwide. Approximately 20 per cent of cases of BC overexpress the human epidermal growth factor receptor (HER2), and HER2-positivity is associated with a significantly worse prognosis. HER2 was first targeted by trastuzumab which significantly improved outcomes, but the efficacy of trastuzumab is limited by acquired and de novo resistance.
The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2 (Figure 1). Aberrant activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapiesand is frequent, with up to 22 per cent of HER2-positive BC having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor administered intravenously, with low nanomolar activity against both PI3Kα and PI3Kβ. Copanlisib has been shown to re-sensitise trastuzumab resistant cell lines to trastuzumab with synergism seen in some cell lines between copanlisib and HER2 targeted therapy.
PantHER is a phase 1b/2 trial that assesses the addition of copanlisib to trastuzumab in patients with histologically confirmed HER2-positive BC that are metastatic or incurable recurrent, following disease progression during, or after, treatment with at least one trastuzumab-based or trastuzumab emtansine (T-DM1)-based treatment regimen in the metastatic or recurrent setting. The phase 1b part of this clinical trial assessed two dose levels of copanlisib (45mg and 60mg on days one, eight, and 15) to determine the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicity (DLT) and therefore the recommended phase 2 dose (RP2D). There were no DLT at either dose level and 60mg of copanlisib was then determined as the RP2D for the combination of copanlisib and trastuzumab. The copanlisib-trastuzumab combination was safe and well tolerated. This part of the trial ran in cancer trials research units in three hospitals around Ireland. The phase 2 part is currently running in cancer trials research units in five hospitals around Ireland and will evaluate the anti-tumour efficacy of the combination in terms of clinical benefit rate (CBR) that is defined as complete response (CR) or partial response (PR) at any time-point on the study; or stable disease (SD) lasting at least 24 weeks based on radiological assessment. Other efficacy measures (such as progression-free survival (PFS), time to treatment failure (TTF), duration of response (DR) and overall survival (OS)) will be evaluated as well as the incidence of cardiotoxicity. We plan to enrol 16 patients with PI3KCA hot spot mutations in the phase 2 part of PantHER.
Panthera is a phase 1b trial that will assess the addition of copanlisib to T-DM1 in patients with unresectable locally advanced or metastatic HER2-positive BC who previously received trastuzumab and a taxane, separately or in combination. There will be three different dose levels of copanlisib according to the dose escalation scheme (dose level 1: 45mg on days one and eight, dose level 2: 60mg on days one and eight, dose level three: 60mg on days one, eight, and 15) to determine the MTD based on the occurrence of DLT. There will be a dose level -1 (45mg on day one only) in case dose de-escalation is needed. Although the main endpoint of this trial is safety, efficacy measures (such as PFS, TTF, DR and OS) will also be evaluated. This trial is a binational study that will run in Ireland (three sites) and Spain (one site) and it is planned to enrol the first patient in early 2019. A maximum of 24 patients with either wild or mutant PI3KCA will be enrolled in this trial.
Both trials have translational sub-studies to examine predictive biomarkers in tumour tissue and blood as well as molecular tumour adaptation to clinical trial therapy.
Addition of a PI3K inhibitor to anti-HER2 therapy is a potential hope to improve outcomes in HER2-positive advanced BC.
References on request