Heterogeneity remains one of the biggest barriers to progress in clinical research. Triple negative breast cancer is an excellent example of this conundrum as I’ve said many times here on this blog – it’s defined not what it is but what it’s not. By that, I mean it’s a broad catch-all for all those women with breast cancer who are essentially ER/PR- HER2- but beyond that are likely other subsets yet to be identified or characterised.
That said, once we have a better sense of what those smaller groups are (from basic and translational research) then progress with targeted therapeutics is much more likely. Why? Because by reducing the inherent variability we increase the chances of success with a given target. If you don’t have a valid and well defined target to aim at then the risks of a negative result in large scale clinical trials are much much higher.
We may also see a new subgroup breast cancers emerge defined solely by their ER/PR- status irrespective of the HER gene. This in itself would be an interesting idea as it lends itself well to the current grouping of patients.
This morning’s coffee browsing in Nature Genetics brought up something that piqued my interest greatly – Haiman and colleagues sent in a Letter reporting on a common risk variant for ER- breast cancer associated with chromosome 5P5, i.e. the TERT-CLPTM1L locus.
The essence of their research was given ER- breast cancer tends to be higher in women of African than European ancestry and confers a poorer prognosis, what common risk alleles could be identified? They collated information from genome-wide association study (GWAS) data in women of African (n=1,004 ER-, n=2,745 controls) and European (n=1,718 ER-, n=3,670 controls) ancestry. Here’s what they found:
“The (5P5) variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer, particularly in younger women (defined as less than 50 years of age).”
In addition, they also observed that:
“In combining the results across all studies (6,009 ER-negative cases and 20,708 controls with genotype data), rs10069690 was significantly associated with an increased risk of ER-negative breast cancer.”
What particularly struck me, however, was a little nugget buried deep in the discussion:
“We found no significant association with rs1006960 among ER- and PR-positive cases when stratified by HER2 status.”
In other words, it is the estrogen receptor status that is the defining characteristic. This suggests that not all triple negative women will behave in the same way, so identifying the factors that are important may change our thinking in how to approach patients in the future.
What do these findings mean?
This study is important because it identifies, for the first time, an aberration ie a common variant at the TERT-CLPTM1L locus that is associated with ER- breast cancer that also tended to occur in younger women. As we begin to dig deeper into the molecular biology of ‘triple negative breast cancer’, I use parentheses loosely here as that definition may one day change with more research, we are likely to:
- Define new subsets of patients who may respond differently
- Identify possible new targets for clinical trials of rationally targeted agents
- Smaller trials will be needed for well-defined subsets that have a greater chance of a good response, this in turn makes an accelerated development potentially possible as we saw recently with crizotinib for ALK-positive lung cancer.
I look forward to following the burgeoning research in this area and suspect that we will see many more groups begin to isolate and identify important aberrations that drive the disease and offer new targets for therapeutic intervention.
Haiman, C., Chen, G., Vachon, C., Canzian, F., Dunning, A., Millikan, R., Wang, X., Ademuyiwa, F., Ahmed, S., Ambrosone, C., Baglietto, L., Balleine, R., Bandera, E., Beckmann, M., Berg, C., Bernstein, L., Blomqvist, C., Blot, W., Brauch, H., Buring, J., Carey, L., Carpenter, J., Chang-Claude, J., Chanock, S., Chasman, D., Clarke, C., Cox, A., Cross, S., Deming, S., Diasio, R., Dimopoulos, A., Driver, W., Dünnebier, T., Durcan, L., Eccles, D., Edlund, C., Ekici, A., Fasching, P., Feigelson, H., Flesch-Janys, D., Fostira, F., Försti, A., Fountzilas, G., Gerty, S., Giles, G., Godwin, A., Goodfellow, P., Graham, N., Greco, D., Hamann, U., Hankinson, S., Hartmann, A., Hein, R., Heinz, J., Holbrook, A., Hoover, R., Hu, J., Hunter, D., Ingles, S., Irwanto, A., Ivanovich, J., John, E., Johnson, N., Jukkola-Vuorinen, A., Kaaks, R., Ko, Y., Kolonel, L., Konstantopoulou, I., Kosma, V., Kulkarni, S., Lambrechts, D., Lee, A., Marchand, L., Lesnick, T., Liu, J., Lindstrom, S., Mannermaa, A., Margolin, S., Martin, N., Miron, P., Montgomery, G., Nevanlinna, H., Nickels, S., Nyante, S., Olswold, C., Palmer, J., Pathak, H., Pectasides, D., Perou, C., Peto, J., Pharoah, P., Pooler, L., Press, M., Pylkäs, K., Rebbeck, T., Rodriguez-Gil, J., Rosenberg, L., Ross, E., Rüdiger, T., Silva, I., Sawyer, E., Schmidt, M., Schulz-Wendtland, R., Schumacher, F., Severi, G., Sheng, X., Signorello, L., Sinn, H., Stevens, K., Southey, M., Tapper, W., Tomlinson, I., Hogervorst, F., Wauters, E., Weaver, J., Wildiers, H., Winqvist, R., Berg, D., Wan, P., Xia, L., Yannoukakos, D., Zheng, W., Ziegler, R., Siddiq, A., Slager, S., Stram, D., Easton, D., Kraft, P., Henderson, B., & Couch, F. (2011). A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer Nature Genetics DOI: 10.1038/ng.985