The KRAS-variant and Second Cancer Risk

curve-up2
second breast cancer3

A second cancer diagnosis is often a concern of cancer patients. Although it seems unfair to have to go through the whole cancer journey again, the good news is that it is not very common to be diagnosed with a second independent cancer. 

Second cancers happen in approximately 1 in 6 cancer survivors.13,14 

The reasons for developing a second cancer are thought to be due to a range of factors, including:

  •  an inherited risk due to hereditary factors
  •  environmental factors, which might have caused your first cancer
  •  cancer treatments, especially in the young

In our previous post, we explained that hereditary breast cancer can be caused by inherited genetic differences, such as BRCA mutations or the KRAS-variant. In this blog post, we will discuss which hereditary factors are associated with an increased risk of developing a second cancer and what can be done to help prevent a second cancer if you carry the KRAS-variant.

Genetic variants and cancer

To understand how the KRAS-variant impacts the risk of a second cancer, we need to define what genetic variants are, how people get them, and the impact they can have on our health.

Any cancer, including a second cancer, is caused by differences in the DNA of a cell that becomes a cancer cell — these differences are called genetic variants. They can be inherited from your parents or can be caused by the environment. 

Genetic variants that are harmful to our health and cause disease are known as “pathogenic genetic variants.” Some well known examples of inherited pathogenic variants are BRCA1 and BRCA2. It has also been shown that women with BRCA variants can be at an increased risk of developing second cancers.4

The KRAS-variant is also an inherited pathogenic genetic variant that has been associated with an increased risk of developing breast, ovarian, and lung cancer, as well as gallbladder cancer and lymphoma (CLL).5,9,26,27,33  Individuals with the KRAS-variant have also been shown to be at an increased risk of developing second cancers.3

The link between the KRAS-variant and second cancers: breast and ovarian

A recent study3 of over 200 women diagnosed with both breast and ovarian cancer found the following:

  • 27.2% had the KRAS-variant
  • 31% had BRCA1 
  • 33% had BRCA2 
  • 9% did not have an identified inherited pathogenic genetic marker

These findings indicate that the KRAS-variant, like BRCA1 and BRCA2, is associated with an increased risk of both breast and ovarian cancer in the same individual. The study also found that of KRAS-variant patients:

  • 64% had breast cancer before ovarian cancer
  • 88% had ovarian cancer after menopause, typically after 52 years of age

Another study9 of breast cancer patients specifically studied the association of the KRAS-variant and a second breast cancer. If a second cancer is diagnosed within 6 months of the first, it is called synchronous. If diagnosed after this time frame, the second cancer is called asynchronous. In the study, KRAS-variant patients were found to be at a significantly increased risk of both types of second breast cancers.

Risk of a synchronous second cancer: 

  • ~7% KRAS-variant patient
  • ~3% Non-variant patient

Risk of a asynchronous second breast cancer:

  • ~8% KRAS-variant patient
  • ~5% Non-variant patient

The results of these two studies indicate that the KRAS-variant predicts an increased risk of multiple cancers in an individual patient.

What you can do to help avoid a second cancer if you have the KRAS-variant

Knowing if you have the KRAS-variant could give you and your doctor the opportunity to consider actions to protect your health. Although we have found that estrogen maintenance can help prevent a first cancer diagnosis for women with the KRAS-variant, estrogen is often not an option after a first cancer diagnosis — especially if the first cancer is breast cancer. In an effort to prevent a second cancer, we describe some potential options below.

Breast Cancer Prevention 

Regular mammograms with ultrasounds

You may consider having more frequent mammograms with ultrasounds as a joint test.19,20 This approach has been shown to be almost as sensitive as other screening methods such as MRI screening.21

MRI screening

You may also consider undergoing breast screening using MRI (Magnetic Resonance Imaging). MRI is a frequently recommended screening method for patients with a high risk of breast cancer.15 

To be eligible to get an MRI, a patient must have a 20% or greater lifetime risk of breast cancer.22 A patient’s risk is determined by several factors34, including:

  • Inherited genetics
    • If you have the KRAS-variant, you have 20-25% lifetime risk of having a first breast cancer,5 and ~2-fold increased risk of a second breast cancer.9 
    • If you have BRCA1 or BRCA2, you have 45-85% lifetime risk of having breast cancer34
  • Personal history of cancer
  • The number of first-degree relatives (mother, sisters, daughters) with breast cancer
  • Age
  • Ethnicity 
  • Reproductive history 

The National Cancer Institute has a Breast Cancer Risk Assessment Tool that can help you calculate your risk. The assessment tool can give you evidence to take to your physician if you want to be considered for an MRI.

Ovarian Cancer Prevention 

Keep seeing your OBGYN

For starters, you may want to consider seeing your OBGYN. Many women stop seeing an OBGYN after they have children, but it is ideal to have an OBGYN do a pelvic exam to screen for ovarian cancer.

Vaginal ultrasound screenings

Your OBGYN may also recommend vaginal ultrasound screenings, which can detect 80-100% of ovarian cancers.16

Consider surgical removal of the ovaries

Ultimately, you may consider surgery in consultation with your physician to remove your ovaries and fallopian tubes, which is referred to as Salpingo-Oophorectomy. Once you are postmenopausal, your ovaries are no longer functional. The surgery is an outpatient procedure considered for high-risk patients. It dramatically reduces the incidence of ovarian cancer.17,18

In summary

Finding out if you are at risk of developing a second cancer may feel overwhelming, especially since you’ve experienced cancer already. However, knowing if you are at an increased risk puts you in the best position to take meaningful steps towards preventing a second cancer, or at a minimum catching it at its earliest and most curable stage.

 


References

  1. https://www.cdc.gov/cancer/breast/triple-negative.htm
  2. https://www.verywellhealth.com/what-is-a-primary-cancer-2249169
  3. Pilarski R, Patel DA, Weitzel J, McVeigh T, Dorairaj JJ, Heneghan HM, Miller N, Weidhaas JB, Kerin MJ, McKenna M, Wu X, Hildebrandt M, Zelterman D, Sand S, Shulman LP. The KRAS-variant is associated with risk of developing double primary breast and ovarian cancer. PLoS One. 2012;7(5):e37891. doi: 10.1371/journal.pone.0037891. Epub 2012 May 25. PMID: 22662244; PMCID: PMC3360659.
  4. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676-89. doi: 10.1086/301749. PMID: 9497246; PMCID: PMC1376944.
  5. Paranjape T, Heneghan H, Lindner R, Keane FK, Hoffman A, Hollestelle A, Dorairaj J, Geyda K, Pelletier C, Nallur S, Martens JW, Hooning MJ, Kerin M, Zelterman D, Zhu Y, Tuck D, Harris L, Miller N, Slack F, Weidhaas J. A 3′-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. Lancet Oncol. 2011 Apr;12(4):377-86. doi: 10.1016/S1470-2045(11)70044-4. Epub 2011 Mar 22. Erratum in: Lancet Oncol. 2011 Jun;12(6):522. PMID: 21435948; PMCID: PMC3488438.
  6. Ratner E, Lu L, Boeke M, Barnett R, Nallur S, Chin LJ, Pelletier C, Blitzblau R, Tassi R, Paranjape T, Hui P, Godwin AK, Yu H, Risch H, Rutherford T, Schwartz P, Santin A, Matloff E, Zelterman D, Slack FJ, Weidhaas JB. A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk. Cancer Res. 2010 Aug 15;70(16):6509-15. doi: 10.1158/0008-5472.CAN-10-0689. Epub 2010 Jul 20. PMID: 20647319; PMCID: PMC2923587.
  7. Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, Weidhaas JB. A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res. 2008 Oct 15;68(20):8535-40. doi: 10.1158/0008-5472.CAN-08-2129. PMID: 18922928; PMCID: PMC2672193.
  8. Bagri PK, Singh D, Singhal MK, Singh G, Mathur G, Jakhar SL, Beniwal S, Sharma N, Kumar HS, Sharma A, Bardia MR. Double primary malignancies: a clinical & pathological analysis report from a regional cancer institute in India. Iran J Cancer Prev. 2014 Spring;7(2):66-72. PMID: 25250152; PMCID: PMC4142942.
  9. McVeigh TP, Jung SY, Kerin MJ, Salzman DW, Nallur S, Nemec AA, Dookwah M, Sadofsky J, Paranjape T, Kelly O, Chan E, Miller N, Sweeney KJ, Zelterman D, Sweasy J, Pilarski R, Telesca D, Slack FJ, Weidhaas JB. Estrogen withdrawal, increased breast cancer risk and the KRAS-variant. Cell Cycle. 2015;14(13):2091-9. doi: 10.1080/15384101.2015.1041694. Epub 2015 May 11. PMID: 25961464; PMCID: PMC4614527.
  10. https://www.hindawi.com/journals/crionm/2020/5691732/
  11. C. G. Moertel, M. B. Dockerty, and A. H. Baggenstoss, “Multiple primary malignant neoplasms. I. Introduction and presentation of data,” Cancer, vol. 14, no. 2, pp. 221–230, 1961.
  12. Manyonda I, Sinai Talaulikar V, Pirhadi R, Ward J, Banerjee D, Onwude J. Could Perimenopausal Estrogen Prevent Breast Cancer? Exploring the Differential Effects of Estrogen-Only Versus Combined Hormone Replacement Therapy. J Clin Med Res. 2022 Jan;14(1):1-7. doi: 10.14740/jocmr4646. Epub 2022 Jan 29. PMID: 35211211; PMCID: PMC8827222.
  13. https://www.cancer.net/survivorship/what-second-cancer#:~:text=Second%20cancers%20are%20becoming%20more,of%20cancer%20in%20the%20past.
  14. Demoor-Goldschmidt C, de Vathaire F. Review of risk factors of secondary cancers among cancer survivors. Br J Radiol. 2019 Jan;92(1093):20180390. doi: 10.1259/bjr.20180390. Epub 2018 Sep 12. PMID: 30102558; PMCID: PMC6435077.
  15. Ren W, Chen M, Qiao Y, Zhao F. Global guidelines for breast cancer screening: A systematic review. Breast. 2022 Aug;64:85-99. doi: 10.1016/j.breast.2022.04.003. Epub 2022 Apr 19. PMID: 35636342; PMCID: PMC9142711.
  16. Kamal R, Hamed S, Mansour S, Mounir Y, Abdel Sallam S. Ovarian cancer screening-ultrasound; impact on ovarian cancer mortality. Br J Radiol. 2018 Oct;91(1090):20170571. doi: 10.1259/bjr.20170571. Epub 2018 Sep 4. PMID: 30102555; PMCID: PMC6350495.
  17. https://www.cuimc.columbia.edu/news/should-women-have-surgery-prevent-ovarian-cancer#:~:text=The%20current%20standard%20of%20care,and%20death%20among%20BRCA1%20carriers.
  18. Coukos G, Rubin SC. Prophylactic oophorectomy. Best Pract Res Clin Obstet Gynaecol. 2002 Aug;16(4):597-609. doi: 10.1053/beog.2002.9305. PMID: 12413937.
  19. Gartlehner G, Thaler K, Chapman A, Kaminski-Hartenthaler A, Berzaczy D, Van Noord MG, Helbich TH. Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk. Cochrane Database Syst Rev. 2013 Apr 30;2013(4):CD009632. doi: 10.1002/14651858.CD009632.pub2. Update in: Cochrane Database Syst Rev. 2023 Mar 31;3:CD009632. PMID: 23633376; PMCID: PMC6464804.
  20. Harada-Shoji N, Suzuki A, Ishida T, et al. Evaluation of Adjunctive Ultrasonography for Breast Cancer Detection Among Women Aged 40-49 Years With Varying Breast Density Undergoing Screening Mammography: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2021;4(8):e2121505. doi:10.1001/jamanetworkopen.2021.21505
  21. Aristokli N, Polycarpou I, Themistocleous SC, Sophocleous D, Mamais I. Comparison of the diagnostic performance of Magnetic Resonance Imaging (MRI), ultrasound and mammography for detection of breast cancer based on tumor type, breast density and patient’s history: A review. Radiography (Lond). 2022 Aug;28(3):848-856. doi: 10.1016/j.radi.2022.01.006. Epub 2022 Feb 8. PMID: 35148941.
  22. https://www.cancer.org/cancer/types/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.html#:~:text=Most%20women%20at%20high%20risk,her%20personal%20circumstances%20and%20preferences.
  23. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet
  24. Metcalfe KA, Finch A, Poll A, Horsman D, Kim-Sing C, Scott J, Royer R, Sun P, Narod SA. Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer. 2009 Jan 27;100(2):421-5. doi: 10.1038/sj.bjc.6604830. Epub 2008 Dec 16. PMID: 19088722; PMCID: PMC2634722.
  25. https://www.breastcancer.org/risk/risk-factors/personal-history
  26. Kazmi HR, Chandra A, Kumar S, Satyam LK, Gupta A, Nigam J, Srivastava M, Mittal B. A let-7 microRNA binding site polymorphism in the KRAS 3’UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population. J Cancer Res Clin Oncol. 2016 Dec;142(12):2577-2583. doi: 10.1007/s00432-016-2254-9. Epub 2016 Sep 12. PMID: 27620744.
  27. Vendramini E, Bomben R, Pozzo F, Benedetti D, Bittolo T, Rossi FM, Dal Bo M, Rabe KG, Pozzato G, Zaja F, Chiarenza A, Di Raimondo F, Braggio E, Parikh SA, Kay NE, Shanafelt TD, Del Poeta G, Gattei V, Zucchetto A. KRAS, NRAS, and BRAF mutations are highly enriched in trisomy 12 chronic lymphocytic leukemia and are associated with shorter treatment-free survival. Leukemia. 2019 Aug;33(8):2111-2115. doi: 10.1038/s41375-019-0444-6. Epub 2019 Mar 14. PMID: 30872781; PMCID: PMC6756038.
  28. Almasan I, Piciu D. Triple Primary Malignancies: Tumor Associations, Survival, and Clinicopathological Analysis: A 25-Year Single-Institution Experience. Healthcare (Basel). 2023 Mar 2;11(5):738. doi: 10.3390/healthcare11050738. PMID: 36900742; PMCID: PMC10001057.
  29. https://seer.cancer.gov/statistics-network/explorer/application.html?site=55&data_type=1&graph_type=2&compareBy=sex&chk_sex_3=3&chk_sex_2=2&rate_type=2&race=1&age_range=1&stage=101&advopt_precision=1&advopt_show_ci=on&hdn_view=0&advopt_show_apc=on&advopt_display=2#resultsRegion0
  30. Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O’Meara ES, Buist DS, Kerlikowske K, van Ravesteyn NT, Trentham-Dietz A, Mandelblatt JS, Miglioretti DL. Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med. 2012 May 1;156(9):635-48. doi: 10.7326/0003-4819-156-9-201205010-00006. PMID: 22547473; PMCID: PMC3561467.
  31. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive#heading-One
  32. https://www.cancer.gov/types/breast/patient/breast-prevention-pdq
  33. Gutiérrez-Malacatt H, Ayala-Sanchez M, Aquino-Ortega X, Dominguez-Rodriguez J, Martinez-Tovar A, Olarte-Carrillo I, Martinez-Hernandez A, C CC, Orozco L, Cordova EJ. The rs61764370 Functional Variant in the KRAS Oncogene is Associated with Chronic Myeloid Leukemia Risk in Women. Asian Pac J Cancer Prev. 2016;17(4):2265-70. doi: 10.7314/apjcp.2016.17.4.2265. PMID: 27221928.
  34. https://bcrisktool.cancer.gov/calculator.html
  35. “Inherited Cancer Risk: BRCA Mutation,” John Hopkins Medicine https://www.hopkinsmedicine.org/health/conditions-and-diseases/breast-cancer/inherited-cancer-risk-brca-mutation

STAY INFORMED

Join our mailing list for news and updates about our research and women’s health!

  • This field is for validation purposes and should be left unchanged.

SHARE   —

mk-home-hero-bottom

Leave a Reply

Your email address will not be published. Required fields are marked *

Disclaimer

Any discussion of medical management options on this website is for general informational purposes only and does not constitute a medical recommendation. All medical management decisions should be made based on consultation between each patient and his or her healthcare professional.

arrow up to top