Breast cancer is the most commonly diagnosed cancer in women accounting for a quarter of cancer cases worldwide. This equates to about 2.3 million women being diagnosed in 2020, with incidence rates increasing worldwide. In addition to this, breast cancer survival rates in both early and metastatic settings are improving hugely, so the number of women living well after breast cancer continues to increase.
Therefore, the impact of breast cancer treatment-associated thrombosis on mortality and morbidity is felt even more keenly. It can lead to early death from venous thromboembolism (VTE), suboptimal cancer treatment, and long-term morbidity from the sequela.
Although VTE in breast cancer is much rarer than in other solid tumors, breast cancer is so common that breast cancer-associated thrombosis makes up approximately 20% of all cancer-associated thrombosis. Therefore, it is essential to identify the relatively rare breast cancer patient at most VTE risk without overfeeding with unnecessary anticoagulation.
In this podcast, Cliona Kirwan, professor in surgical clinical trials at the University of Manchester, talks about thrombosis and coagulation management in breast cancer.
Summary podcast: Thrombosis and coagulation in the contemporary management of breast cancer
Cliona Kirwan, Professor in Surgical Clinical Trials, University of Manchester
Full podcast: Thrombosis and coagulation in the contemporary management of breast cancer
Cliona Kirwan, Professor in Surgical Clinical Trials, University of Manchester
Full podcast trascript:
Contemporary breast cancer treatment for associated thrombosis.
Breast cancer is the most commonly diagnosed cancer in women, accounting for a quarter of all cancer cases worldwide. This equates to about 2.3 million women being diagnosed in 2020, with age-standardized incidence rates continuing to increase worldwide.
Globally, age-standardized mortality rates are decreasing. For example, only 40% of women were surviving after ten years in the UK in 1970, whereas, by 2010, 78.4% were surviving for 10 years.
Approximately 8 million women are currently alive worldwide following a breast cancer diagnosis within the previous five years.
There have also been enormous improvements in metastatic breast cancer care with a five-year survival rate for women in first world countries of about 25 to 28%, with the median survival increasing by 80% from 1990 to 2010.
The vast majority of cancers are associated with an increased risk of venous thromboembolism compared to the normal population, and breast cancer is no exception.
Compared to normal controls, cancer patients have been eight to nine-fold risk of venous thromboembolism within a year of cancer diagnosis, and venous thromboembolism in the presence of cancer is associated with a three-fold risk of death.
However, the risk of venous thromboembolism with breast cancer is much lower than in other cancers, with breast cancer being in the bottom quartile of cancers if cancer type is ranked by cancer-associated thrombosis frequency.
With, for example, pancreatic cancer thrombosis being 10 times more common, and brain or upper GI [gastrointestinal] thrombosis about four or five times more common than breast cancer-associated thrombosis.
But breast cancer is so common, still many women develop cancer-associated thrombosis during breast cancer treatment.
In fact, almost 20% of all cancer-associated thrombosis are breast cancer-associated thrombosis because breast cancer is so common.
And this can severely impact women’s quality of life and even survival, even through death from venous thromboembolism or through subsequent suboptimal cancer treatment.
Indeed, the negative impact of breast cancer on survival is ironically most pronounced in early-stage disease, being associated with a two-fold risk of death and a two-year risk of death being doubled in metastatic breast cancer but increased by fivefold in local disease, which reflects the otherwise excellent prognosis of breast cancer.
So venous thromboembolism in breast cancer can really impact on quality of life in women who otherwise will do brilliantly.
The risk of venous thromboembolism is greatest around the time of diagnosis, and primary all metastatic diseases, with for example rate of venous thromboembolism within the first six months of a new diagnosis being double that in the second six months.
This implies that breast cancer treatment is instrumental in the development of breast cancer-associated thrombosis.
As with other cancer, venous thromboembolism risk increases with age, for example, with the hazard ratio for venous thromboembolism for metastatic breast cancer of six and local-regional breast cancer of two compared to cancer localized to the breast only.
However, this is undoubtedly partly a reflection of the more aggressive intensive extended treatments that are associated with increased breast cancer stage.
The incidence of breast cancer-associated thrombosis has almost doubled from 1997 to 2005, corresponding with increasing survival changes in treatment, particularly chemotherapy, and targeted therapies, and improving imaging and awareness of venous thromboembolism.
In terms of early breast cancer, treatment is intended to be curative whilst minimizing harm.
The mainstay of breast cancer is surgery with adjuvant or neoadjuvant treatments commonly including endocrine therapy, radiotherapy, chemotherapy, and targeted therapies.
Although surgical techniques for breast cancer are becoming more complex in terms of oncoplastic procedures, including reconstruction, breast cancer is still relatively highly traumatic. For example, with no internal body cavity dissection.
The risk of venous thromboembolism is double within one month of breast surgery; however, venous thromboembolism rates are still low at less than 1% except possibly with flat-based reconstruction estimated between 1.2 to 1.4%.
This small risk needs to be balanced against the significant risk of bleeding within general hematoma that requires reoperation, occurring in about 2% of patients irrelevantly of anticoagulation.
One of the challenges is that there are no risk assessments scores such as Caprini for informing venous thromboembolism prophylaxis to the lower risk nature of breast cancer surgery compared to other solid tumors.
So, there is a very real need for breast cancer-specific risk assessment tools for surgery.
I forgot chemotherapy. Breast cancer patients receiving chemotherapy have an estimated 11-fold risk of venous thromboembolism compared to those not receiving chemotherapy, with this risk maintained for at least three months.
Increasingly we are delivering breast cancer chemotherapy, particularly in higher stage diseases than in the neoadjuvant setting.
This means patients are undergoing surgery only three to six weeks after completion of chemotherapy.
Surgery performed within two weeks from chemotherapy is associated with an enormous 5-fold increase in risk for venous thromboembolism compared to upfront surgery.
Similar to surgery, risk scores for chemotherapy-induced venous thromboembolism, such as the Khorana score, were developed in a mixed solid tumor population.
The cancer site is heavily weighted in these, and breast cancer is particularly loaded for venous thromboembolism compared to other tumors is in the development of those tools these tools may well lack discriminating ability in breast cancer. Because as far as I’m aware they have not been tested in the full breast population.
Indeed, these scores have only four criteria unrelated to the cancer site; so, for breast cancer patients to be categorized as high-risk as a high risk they have to score in three out of four of these.
Now turning to endocrine therapy, fortunately, 75% of breast cancers are estrogen-receptor-positive and can be treated with endocrine therapy.
Selectively estrogen receptor modulators, such as tamoxifen, are used in premenopausal women and the aromatase inhibitors, such as anastrozole, letrozole, and exemestane, are primarily used in postmenopausal women.
Tamoxifen for breast cancer in both women and men is associated with an up to the seven-fold increased risk of venous thromboembolism, with this risk exacerbated by concurrent chemotherapy.
So, this is in part why adjuvant chemotherapy is given far to commencement of endocrine therapy.
The endocrine-therapy-associated risk of thrombosis is very frontloaded and seemed to be greatest within the first three months of commencing tamoxifen, with a hazard rate of over 5 compared to free treatment.
However, the risk is ongoing, and this has been demonstrated by switching adjuvant breast cancer trials where the tamoxifen arm gets switched to an aromatase inhibitor after two years and the other stays on tamoxifen, with the risk remaining doubled in the tamoxifen arm compared to aromatase inhibitors.
And even in the preventative setting where there is no breast cancer, tamoxifen is associated with an approximately two-fold increase in the risk of venous thromboembolism.
Aromatase inhibitors are associated with a 50% lower risk of venous thromboembolism compared to tamoxifen, which actually may equate to not being thrombogenic at all.
However, the only trials of aromatase inhibitors versus no treatment are in the preventative setting, again where there’s no presence of cancer, and here anastrozole had the equivalent risk of venous thromboembolism compared to placebo.
The need to stop tamoxifen in the perioperative setting is quite unclear given that an endocrine therapy break is unlikely to have a significant negative oncological impact; it does seem sensible to stop tamoxifen especially if there are other risk factors for venous thromboembolism such as obesity, age, and particularly thrombogenic surgeries, such as, for example, hip and knee replacement.
Talking about other treatments. Bisphosphonate is used to mitigate against the osteoporotic effects of aromatase inhibitors or as an adjective endocrine therapy to prevent or treat bone metastases, and there is actually some evidence to suggest an association with venous thromboembolism however it is weak.
Targeted treatment is an enormous area of interest and success in breast cancer. In only 20 years the development of targeted anti-HER2 therapy has revolutionized HER2-positive breast cancer, which makes up about 15% of breast cancers.
HER2-directed therapy effectively now negates the negative prognostic impact of HER2-positive disease.
And although precise published results are economical for venous thromboembolism data, there doesn’t appear to be any hint of thrombogenic effect with anti-HER2 therapy.
Apart from anti-HER2 targeted therapies, the new game-changers for breast cancer treatment are CDK-46, PD-L1 immune checkpoint inhibitors, PARP inhibitors, and possibly mTOR and tyrosine kinase inhibitors.
Today the only targeted therapy that appears to be associated with venous thromboembolism is CDK-46 inhibitors, but it seems to be a class effect with a meta-analysis suggesting a two and a half fold increased risk of venous thromboembolism with CDK-46 inhibitors in breast cancer treatment.
Although two studies report an association between radiotherapy and venous thromboembolism, neither report describe radiotherapy treatment and clearly radiotherapy for brain and pelvic bone metastasis will have a very different VENOUS THROMBOEMBOLISM effect than chest whole adjvant radiotherapy.
So, I personally suspect that the prothrombotic effects of radiotherapy and breast cancer are limited to specific high-risk anatomical sites.
But it’s important to recognize that, historically, there has been a lack of recognition of venous thromboembolism risk by breast cancer by clinicians, particularly relating to breast cancer because of the relative perceived low risk in breast cancer.
This is potentially exacerbated by the fact that cancer therapy is often delivered in tertiary centers with acute thromboembolism is likely to present to a local hospital.
So outside of clinical trials, there’s still ongoing risk of underreporting of truth rates of breast-associated thrombosis.
I think the real area of research needs is developing risk assessment tools that are specific to breast cancer.