High Microvascular Density in Breast Cancer May be Associated With Bevacizumab Efficacy

November 10, 2015
Christin Melton, ELS

Findings from a recent study suggest that women whose breast cancers have a higher proportion of blood vessels may benefit more from neoadjuvant treatment with bevacizumab than women whose tumors have a lower density of blood vessels.

Rakesh Jain, PhD

Findings from a recent study by Jain et al published inPNASsuggest that women whose breast cancers have a higher proportion of blood vessels may benefit more from neoadjuvant treatment with bevacizumab (Avastin) than women whose tumors have a lower density of blood vessels.1

Bevacizumab binds to vascular endothelial growth factor (VEGF), thereby preventing it from binding to the VEGF receptor (VEGFR) and triggering new blood vessel formation. In 2011, the FDA rescinded approval of bevacizumab (Avastin) as a treatment for metastatic breast cancer.2The FDA concluded that studies completed after the agency had granted bevacizumab accelerated approval showed the drug’s risks outweighed its potential benefits; however, some breast cancers respond very well to bevacizumab therapy. Jain et al used multiple methods to look for predictors of response to neoadjuvant bevacizumab in women with nonmetastic breast cancer.

The study enrolled women (median age, 48 years) with triple-negative breast cancer (TNBC; n = 21) or high-risk hormone receptor—positive breast cancer (HRBC; n = 78).1Participants underwent a baseline biopsy, which was followed by a single dose of bevacizumab (10 mg/kg) and another biopsy. They were then treated with bevacizumab plus chemotherapy for several weeks before undergoing surgical resection 4 to 8 weeks after the final bevacizumab dose.

Comparisons of baseline and posttreatment biopsies showed that women with TNBC were much more likely to achieve pathologic complete response (pCR) than women with HRBC (52% vs 6%, respectively;P<.0001). Women with TNBC also had significantly greater reductions in tumor burden with treatment than women with HRBC (P<.0001). Most of the pCRs in the HRBC cohort (11 of 13) occurred in women with basal-like tumors.

In the TNBC cohort, the investigators observed a significantly higher pathological response rate for women with lower levels of soluble VEGFR 1 than for women with higher levels after a single dose of bevacizumab (P= .0033). In the overall population, pathologic response correlated significantly with baseline microvascular density (MVD). Women with high pretreatment MVD were significantly more likely than women with low baseline MVD to respond to treatment (P= .0005).

Tumor blood vessels are typically abnormal, with structural and functional defects.3Examination of the tumor biopsies showed that bevacizumab decreased the density of immature, pericyte-deficient vessels, which tend to be leaky and more permeable, but did not affect the density of pericyte-covered mature vessels.1The authors theorized that bevacizumab may also have recruited pericyte cells to some of the immature vessels, promoting their maturation and normalization. Further analyses detected increases in markers of vascular normalization that correlated positively with pathologic response, particularly in women with high baseline MVD.

Abnormal immature blood vessels are less effective at delivering nutrients, and they contribute to hypoxia in the tumor tissue. “Hypoxia is known to make tumors more invasive and metastatic, create an immune-suppressive microenvironment in tumors, and confer resistance to many therapies,” explained study co-author Rakesh Jain, PhD, in an interview withTargeted Oncology. Jain is the Andrew Werk Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School in Cambridge, Massachusetts, and the director of the Edwin L. Steele Laboratory for Tumor Biology at Massachusetts General Hospital in Boston. He and his associates have been researching their hypothesis that antiangiogenic agents like bevacizumab can normalize abnormal tumor vessels and make them more effective at delivering chemotherapy or radiotherapy to the tumor.

“Increased perfusion may enhance access or delivery of therapeutic agents into tumors and, more importantly, alleviate hypoxia. [This] may slow tumor progression and make many therapies more effective, including radiation, certain chemotherapy drugs, and immunotherapeutics,” Jain said.

Jain first proposed that anti-VEGFR therapy could be used to normalize tumor vasculature and improve delivery of neoplastic agents in 2001.3The current study lends support to this hypothesis and sheds light on why some breast cancers respond well to bevacizumab, whereas others show little response.

According to Jain, “The findings reveal that normalization requires a high vascular density prior to treatment. Because many breast cancers are relatively poorly vascularized, these tumors may not respond to the addition of bevacizumab to chemotherapy.” He said it is not clear why baseline TNBCs tend to have higher MVD at baseline than HRBCs. “However, it is well established that the oncogenic drivers are different between HRBCs and TNBCs. So while the host (breast) tissue is similar, the tumors are vastly different, which may account for the differences in MVD.”

The findings suggest bevacizumab and other antiangiogenic agents may have a role in treating some breast cancers. “Bevacizumab is no longer approved by the FDA for breast cancer, but it clearly has activity in a subset of patients,” Jain said. “Our study, once validated independently, may provide a path forward to identify and select these patients for bevacizumab treatment using widely available tissue analyses and tumor imaging techniques.”

References

  1. Tolaney SM, Boucher Y, Duda DG, et al. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.PNAS. doi: 10.1073/pnas.1518808112.
  2. FDA commissioner removes breast cancer indication from Avastin label [news release]. Silver Spring, MD: U.S. Food and Drug Administration; November 9, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279485.htm. Accessed November 9, 2015.
  3. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy.Nat Med. 2001;7(9):987-989. doi:10.1038/nm0901-987.