Primary Immunoprevention: The Great Unmet Need for Controlling Breast Cancer

OncologyOncology Vol 30 No 5
Volume 30
Issue 5

Perhaps we can now hope that primary immunoprevention of cancers that are engaged as people age may receive the attention, support, and legitimacy that will soon result in similar breakthrough stature.

Oncology (Williston Park). 30(5):486–487.

Since their inception in the late 18th century, vaccines have been used predominantly as prophylactic agents, and their greatest clinical benefit has been in preventing diseases caused by pathogens.[1,2] In fact, when used as treatment after symptoms manifest, traditional pathogen-targeted vaccines fail to enhance pathogen clearance or alleviate disease activity.[3] Thus, it appears safe to say that vaccines work best when providing pre-emptive immunity.

Despite the fact that the effectiveness of vaccines for disease prevention has been repeatedly proven, cancer vaccines have been used predominantly as treatment agents administered after the emergence of established growing tumors. The notable exceptions to the dominance of the treatment paradigm for cancer vaccination seem confined to cancers such as those in the liver and cervix that are caused by pathogens.[4,5]

Breast cancer vaccination is particularly dominated by this treatment paradigm in that vaccine researchers use the word “prevention” almost exclusively “…to avoid or defer the complications of diseases after they have developed…,”[6] and apply such tertiary prevention strategies to prevent recurrence or invasiveness of pre-existing breast tumors. Despite the need for such tertiary prevention strategies, one could argue that the greatest unmet need for controlling breast cancer is the development of a vaccine that provides primary prevention of breast tumor growth for healthy, tumor-free women.

It is a matter of speculation as to why primary immunoprevention is not a high priority for control of breast cancer, but there is no doubt about its nonpriority status as reflected by the established funding structure that clearly favors cancer treatment over cancer prevention. The most recent available fiscal data from the National Cancer Institute indicate that actual spending for treatment research was 3.4 times greater than spending for cancer prevention.[7] Even though primary immunoprevention for breast cancer often fails to get the funding support that its potential impact may command, it is still an active area of investigation involving a handful of diehard enthusiasts, so perhaps a brief overview of actively pursued approaches may be in order here.

Human mammary tumor viruses (HMTV) have been proposed as potential targets for inducing primary immunoprevention of breast cancer, and perhaps the most studied variant of HMTV is a nongenomic infectious retrovirus that has > 95% homology with the oncogenic mouse mammary tumor virus and is detected in about 38% of human breast tumor tissues.[8,9] The endogenous retrovirus type K (HERV-K) family members whose envelope proteins are expressed on the surface of human breast cancer cells may also serve as potential vaccine targets for primary prevention.[10] As suggested by Salmons et al in 2013,[11] resolution of a possible viral role in human breast cancer tumorigenesis awaits definitive studies showing viral-induced malignant transformation and tumor formation in vivo.

Given the current uncertainty implicating a definitive oncogenic virus for human breast cancer, what nonpathogenic proteins can substitute as vaccine targets for developing primary immunoprevention of breast cancer? To this end, Dr. Olivera Finn has pioneered the concept of vaccinating against immunologically available primary peptide sequences of MUC1, a protein expressed with a low level of glycosylation in many human tumors and also expressed ubiquitously in many normal tissues but at heavily glycosylated levels that preclude immunologic availability.[12] Tiriveedhi and colleagues have proposed vaccination against mammaglobin A expressed in the majority of human estrogen receptor–positive breast tumors, as well as in a small handful of normal tissues.[13] Several investigators have proposed vaccination against human epidermal growth factor receptor 2 (HER2) and a variety of other similar ubiquitously found proteins that are expressed at high levels in some breast tumors, but are presumably expressed at low nonimmunogenic levels in many normal tissues.[14] Dr. Stephen Johnston has proposed vaccination against a finite number of immunogenic frameshift neoantigens suspected to be broadly expressed in most human breast tumors.[15,16] We have proposed that tissue-specific self-proteins that are “retired” from expression in normal tissues as we age, but are expressed in emerging tumors, may substitute as vaccine targets for unavailable pathogens for primary immunoprevention of breast cancer.[17] To this end, we have identified α-lactalbumin as a retired breast-specific self-protein not expressed at immunogenic levels in any normal tissues with age, but expressed in the majority of triple-negative breast cancers (TNBCs), the most aggressive form of breast cancer and the most predominant form occurring in women with BRCA1 mutations who have high genetic risk and thus the greatest need for a preventive vaccine.[18,19]

Each of these approaches for primary immunoprevention of breast cancer has strengths and weaknesses, and it is far from clear at this early point which of these proposed approaches will prove to be most successful in providing safe and effective pre-emptive immunity and protection against the development of breast cancer. However, it may be worth considering several issues as these different approaches proceed through clinical testing. First, breast cancer is clearly a complex disease involving many subtypes,[20] and this complexity may predispose to a need for a multivalent preventive vaccine against sufficient targets expressed in the known multitude of different breast cancer variants. For example, one vaccine target may be effective in preventing estrogen receptor–positive breast cancer (eg, mammaglobin A), whereas another may be useful in preventing TNBC (eg, α-lactalbumin). A single vaccine that incorporates multiple targets may be necessary to control a broader array of breast cancer subtypes, as indicated by Shen et al in their common pooled neoantigen strategy.[16]

In addition, it is difficult to ignore the substantial emphasis on vaccinating against HER2 and other self-proteins that are ubiquitously expressed in numerous normal tissues. The immune response elicited to such globally expressed self-proteins is often subdominant or cryptic because of efficient self-reactive T-cell repertoire deletion, resulting in a predominance of low-affinity T cells incapable of targeting clinically relevant immune responses. Nevertheless, this excessive focus on HER2 and related systemically expressed self-proteins persists in the field of breast cancer vaccination, along with the common use of vaccine adjuvants that generate a predominant type 1 T helper (Th1)-like immunity that precludes the incorporation of the robust proinflammatory features of Th17 and Th9 responsiveness implicated in optimized tissue destruction in response to self-proteins.[21,22]

Finally, it remains unexplained in the Mittendorf et al review in this issue of ONCOLOGY[23] how a vaccine targeted against HER2 could be most effective against HER2-negative breast tumors. Indeed, our own direct experience indicates that increased T-cell infiltration and enhanced tissue destruction occurs when tissues express high levels of immune-targeted self-proteins.[24] In any event, cancer immunotherapy has come a long way, having been recognized for breakthrough status by the editors of Science in 2013.[25] Perhaps we can now hope that primary immunoprevention of cancers that are engaged as people age may receive the attention, support, and legitimacy that will soon result in similar breakthrough stature.

Financial Disclosure:Dr. Tuohy is the primary inventor with intellectual property related to α-lactalbumin vaccination. He has licensed his inventions to Shield Biotech, Inc, for the purpose of commercialization and stands to benefit financially if these inventions are tested successfully in clinical trials. Shield Biotech, Inc, had no role in the writing or decision to publish this commentary.


1. Centers for Disease Control and Prevention. Ten great public health achievements-United States, 1900-1999. Morb Mortal Wkly Rep. 1999;48:241-3.

2. Centers for Disease Control and Prevention. Impact of vaccines universally recommended for children--United States, 1990-1998. Morb Mortal Wkly Rep. 1999;48:243-8.

3. Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007;298:743-53.

4. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997;336:1855-9.

5. Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol. 2012;10:681-92.

6. Woolf SH, Husten CG, Lewin LS, et al. The economic argument for disease prevention: distinguishing between value and savings. Partnership for Prevention, 2009. Accessed April 7, 2016.

7. National Cancer Institute Program Structure Fiscal Year 2014. Funding allocated to major NCI program areas. Accessed April 7, 2016.

8. Holland JF, Pogo BG. Mouse mammary tumor virus-like viral infection and human breast cancer. Clin Cancer Res. 2004;10:5647-9.

9. Pogo BG, Holland JF, Levine PH. Human mammary tumor virus in inflammatory breast cancer. Cancer. 2010;116:2741-4.

10. Wang-Johanning F, Rycaj K, Plummer JB, et al. Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J Natl Cancer Inst. 2012;104:189-210.

11. Salmons B, Gunzburg WH. Revisiting a role for a mammary tumor retrovirus in human breast cancer. Int J Cancer. 2013;133:1530-5.

12. Kimura T, Finn OJ. MUC1 immunotherapy is here to stay. Expert Opin Biol Ther. 2013;13:35-49.

13. Tiriveedhi V, Fleming TP, Goedegebuure PS, et al. Mammaglobin-A cDNA vaccination of breast cancer patients induces antigen-specific cytotoxic CD4+ICOShi T cells. Breast Cancer Res Treat. 2013;138:109-18.

14. Milani A, Sangiolo D, Montemurro F, et al. Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives. Ann Oncol. 2013;24:1740-8.

15. Shen L, Sykes K, Johnston SA. Frameshift peptides as prophylactic cancer vaccine antigens. Cancer Res. 2012;72(suppl 8):abstr 1570.

16. Shen L, Lee H, Sykes K, Johnston SA. Progress towards developing a universal, prophylactic cancer vaccine. Cancer Res. 2013;73(suppl 8):abstr 469.

17. Tuohy VK. Retired self-proteins as vaccine targets for primary immunoprevention of adult-onset cancers. Expert Rev Vaccines. 2014;13:1447-62.

18. Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26:4282-8.

19. Comen E, Davids M, Kirchhoff T, et al. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi women. Breast Cancer Res Treat. 2011;129:185-90.

20. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.

21. Martin-Orozco N, Muranski P, Chung Y, et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009;31:787-98.

22. Purwar R, Schlapbach C, Xiao S, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med. 2012;18:1248-53.

23. Mittendorf EA, Peoples GE. Injecting hope-a review of breast cancer vaccines. Oncology (Williston Park). 2016;30:475-81, 485.

24. Jaini R, Popescu DC, Flask CA, et al. Myelin antigen load influences antigen presentation and severity of central nervous system autoimmunity. J Neuroimmunol. 2013;259:37-46.

25. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432-3.

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