Contemporary breast cancer treatment-associated venous thromboembolism

Breast cancer patients have a three-to four fold increased risk of venous thromboembolism (VTE) when compared to women of an equivalent age without cancer^[1], equating to approximately 1-2% of all breast cancer patients^[2]. More importantly, breast cancer treatment, in particular surgery, chemotherapy and endocrine therapy, significantly escalates this risk further^[3]. VTE is known to be associated with both disease recurrence and reduced survival^[4–6], but in itself is a devastating complication^[6]. Breast cancer treatment-associated VTE rates have dramatically risen over the last couple of decades ^[7]. This is potentially due to the increased diagnosis of asymptomatic VTE secondary to the enhanced sensitivity of imaging techniques for cancer staging; more aggressive cancer therapies; or a combination of both^[1]. This increased rate has led to a magnified awareness of cancer treatment-associated VTE than previously seen^[8], yet the optimal thromboprophylaxis mechanism, particularly for patients undergoing surgery, is not entirely clear^[9].

The reported incidence of VTE following breast surgery for malignancy ranges from 0.16-0.4%. It is higher for mastectomy, with or without reconstruction, than for breast conserving surgery (BCS)^[10–13]. A retrospective cohort study of 13,202 patients reported that surgery, in the form of mastectomy or BCS, increased the rate of VTE (HR 2.2) as compared to those not undergoing surgery, but only in the first month after discharge^[7]. However, in the Million Women Study, for women undergoing surgery for cancer, the risk of VTE remained elevated for at least 12 weeks post-cancer surgery^[14], with a relative risk at 6 weeks of 92, falling to 53 at 12 weeks and 6 at 1 year^[14]. A recent American College of Surgeons National Surgical Quality Improvement Programme analysis reported an overall VTE incidence within 30 days of surgery to be 0.13% for BCS, 0.29% for mastectomy alone, 0.41% for delayed reconstruction and 0.52% for mastectomy with reconstruction^[10]. These findings were similar to Momeni et al^[15] who reported rates of 0.47% for BCS, 0.59% for mastectomy alone, 0.33% with mastectomy and implant reconstruction and 0.71% for mastectomy with autologous reconstruction^[15]. Delayed autologous reconstruction after mastectomy has been reported to be associated with even higher VTE rates. The VTE rate was 4% in one study despite thromboprophylaxis^[16] and 31.4% in the absence of thromboprophylaxis in a smaller study^[17].

The current American College of Chest Physicians (ACCP) recommendations for breast surgery in relation to VTE are detailed within the general surgery section of the document^[18]. Mastectomy is considered low risk for VTE, but age >60 and operation time ≥ 2 hours are identified as patient-specific risk factors, and commonly apply to breast surgery patients^[18]. Given the lack of evidence for the risk-benefit profile of chemoprophylaxis, the American Society of Breast Surgeons consensus statement supports an individualised risk assessment strategy^[19], as does the National Institute for Health and Care Excellence in the United Kingdom^[20]. The Caprini score, stratifies the risk of VTE in surgical patients^[21]. In a study of 522 consecutive mastectomy patients (67% of whom underwent immediate implant-based reconstruction), 83% had a Caprini score of 5-7, and were therefore recommended preoperative chemoprevention, that was then continued postoperatively until discharge. VTE and haematoma rates were both low at 0.2% and 3.4% respectively. However, compliance with chemoprevention was only 60%. Interestingly, the American Society of Breast Surgeons consensus statement, which has been adopted by the Association of Breast Surgery in the UK, support early ambulation and mechanical VTE prophylaxis in the majority of breast surgery patients^[19,22].

The increased VTE risk with chemotherapy has been confirmed in two retrospective cohort studies^[7,23] and one prospective study^[24]. Walker et al^[7] presented an adjusted hazard ratio (HR) of 2.2 in those receiving chemotherapy as compared to those not, and Brand et al^[23] stated a HR of 1.8. This increased risk was most significant during chemotherapy (HR 10.8) and for the first month after therapy cessation (HR 8.4), although some increased risk remained up to three months after the cessation of therapy before returning to baseline^[7]. In a prospective study of breast cancer chemotherapy patients undergoing duplex ultrasound screening, VTE was diagnosed in 17% of those with advanced breast cancer and 8% of those with early breast cancer^[24]. The majority of these events occurred within 3 months of chemotherapy^[27,4]. Although chemotherapy induces vascular endothelial cell activation, this does not appear to be the primary mechanism for chemotherapy-induced VTE^[25].Chemotherapy-induced apoptosis may enhance hypercoagulability and initiate VTE^[25]. Central-venous catheters are frequently required in breast cancer patients receiving chemotherapy, and are associated with a doppler ultrasound detected VTE cumulative probability of 9.6% at 3 months and 11.5% at 6 months, with 20% being symptomatic^[26].

Endocrine therapy can enhance prothrombotic tendency independent of other treatments^[27]. In two retrospective cohort studies, endocrine therapy was found to increase the risk of VTE during the first three month ^[7,28]. Walker et al reported a doubling in VTE risk, with this risk being increased five-fold in the first three months of treatment^[7]. Blom et al reported a 1.8 times increased risk in those without distant metastases and a 1.3 times increased risk in those with metastases (28). In the former study, the risk of VTE was attributable to tamoxifen only, with no increased risk associated with Aromatase Inhibitors (AIs)^[7]. This is consistent with Xu et al who reported a 41% lower VTE risk with AIs as compared to tamoxifen^[29]. Interestingly, in patients who underwent delayed breast reconstruction including free and pedicled flaps, fat grafting and tissue expander/ implant based reconstructions; there was no difference in VTE rate between those on endocrine therapy (including, tamoxifen, AIs and fulvestrant) and those not^[30,31]. The increased VTE risk with tamoxifen is also applicable to male breast cancer patients^[32]. In a study of 218 male patients with early breast cancer, 97.7% were oestrogen receptor positive and received tamoxifen therapy^[32]. The cumulative VTE risk was 11.9%, with 80% of these events occurring within the first 18 months after the initiation of treatment^[32].

In conclusion, breast cancer treatment-associated VTE is more frequently diagnosed due to modern breast cancer management techniques; particularly the advent of complex microvascular free-flap breast reconstructions, more aggressive chemotherapy regimens and improved cancer staging images. Awareness among clinicians of this risk is imperative in ensuring appropriate thromboprophylaxis, that balances the risk of chemoprophylaxis with VTE associated morbidity and mortality.

References

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