Difficult cancer treatment choices

As We See It: Difficult Cancer Treatment Choices

When confronting breast cancer, women face difficult choices relating to side effects including bone fractures and harsh menopausal miseries. New data reveal an optimal time to discontinue use of estrogen-blocking drugs to mitigate side effects without compromising treatment efficacy.

By William Faloon.

William Faloon
William Faloon

In the United States this year, about 43,000 women will suffer agonizing deaths from metastatic breast cancers.1

From the day of diagnosis, women face difficult choices relating to treatments that inflict side effects, with none guaranteed to elicit a cure.

Be it radiation, chemotherapy, surgery, hormonal and/or checkpoint inhibitors, there are a myriad of known challenges, such as future cancer risks, heart damage, and cognitive impairment (chemo brain).2-7

A difficult choice for women with estrogen-receptor positive tumors is how long to stay on drugs that deplete their body of estrogen. These drugs are called aromatase inhibitors.8

Estrogen depletion using aromatase inhibitors reduces risks of breast cancer recurrence and metastasis.5,9 But these drugs deprive the women's bodies of essential functions such as maintaining bone density, along with causing menopausal symptoms like sleep deprivation and weight gain that can be life shortening.10,11

The risk of estrogen-receptor positive breast cancer recurrence continues far beyond the typical five-year standard mark. For some, the risk of recurrence remains elevated for 15 years or more.5

This long-term risk of recurrence has caused a conundrum as it relates to how many years a woman should continue taking an aromatase inhibitor, and what can be done to mitigate the side effects of estrogen depletion.5,10,12

Recent findings provide a rationale not to overly extend the time that an aromatase inhibitor is used.10 Other studies reveal how to reduce bone fractures while lowering risks of cancer recurrence.12

This article describes some of these safer approaches to the "difficult choices" faced by breast cancer patients.

When an abnormal mass is detected by mammography, ultrasound, MRI, or feeling a breast lump, the next step is a biopsy to determine if it is cancer and what type of cancer cells are present.

The deadliest common breast tumor type is called triple negative. This means that there are no cell receptors detected for estrogen, progesterone or HER2, thus making it "triple (receptor) negative."13

Without a specific growth-promoting receptor, there are limited approaches to target triple negative tumors other than surgery followed by whole-breast radiation and aggressive chemo.13 About 10%-15% of breast tumors are triple negative with poor outcomes if they become metastatic.14

Another 15%-20% of breast cancers are HER2+, and there are targeted drugs like Herceptin® that improve survival.15 Over time, these drugs lose effectiveness as cancer cells mutate to become less reliant on the HER2 receptor. (HER2 is the acronym16 for human epidermal growth factor receptor 2.)16

The best news for a breast cancer patient is to learn they have the easier-to-treat estrogen receptor positive (ER+) or estrogen/progesterone receptor positive (ER/PR+) type.17

Both ER+ and ER/PR+ breast tumors respond to whole-body estrogen depletion (using an aromatase inhibitor drug) and/or drugs like tamoxifen that block the ability of estrogen to bind to its receptor on breast cells.13,18,19

These drugs come with side effects that include joint pain, cognitive impairment, weight gain and other menopausal miseries. Aromatase inhibitors deplete bone density and increase fracture risk.10

These anti-estrogen drugs do, however, significantly improve ER+ cancer survival rates and there are ways to mitigate some of their side effects.20

How Long Should Aromatase Inhibitors be Used?

About 80% of breast tumors are ER+ or ER/PR+ and respond well initially to anti-estrogen drugs.21

These favorable responses have caused some oncologists to suggest long-term use of aromatase inhibitors to reduce risks of cancer recurrence/metastasis.

A large-scale study published in the New England Journal of Medicine looked at women prescribed an aromatase inhibitor and/or tamoxifen for five years.10

The clinical researchers found that after the initial five years of anti-estrogen drug treatment, two additional years of aromatase inhibition provided similar anti-cancer benefits as five additional years of anti-estrogen drug therapy.

They also showed that the risk of bone fracture was 35% higher in women taking an aromatase inhibitor for five additional years (compared to two additional years).

Women in the two additional years' treatment group experienced about 60% fewer cases of osteoarthritis compared to the five additional years' treatment arm.

The bone fractures reduction effects shown in the shorter-term use of the estrogen-depleting aromatase inhibitor occurred regardless of the use of skeletal supportive drugs I discuss next.

Protect Against Skeletal Degeneration

Estrogen helps maintain bone density by inhibiting the excess removal (resorption) of bone. It also plays a role in healthy bone remodeling.22

When estrogen depletion occurs during menopause, risks of osteoporosis and bone fractures increase.23

When estrogen is virtually eliminated using aromatase inhibitor drugs, rapid bone loss often ensues.24,25 In addition to skeletal fractures, mounting evidence suggests that as bone is excessively broken down, it releases growth factors that can stimulate residual cancer cell propagation.26

Maintaining bone density is an essential component of breast cancer treatment and there are choices as to which class of skeletal-supporting drug to use.27

The bisphosphonate class of drugs (Fosamax®, Aredia®, Zometa®, et al.) have proven bone-building properties but induce side effects in some people.28,29

Another bone-building drug called Prolia® (generic name denosumab) has also demonstrated favorable results but works differently than bisphosphonates.

Researchers compared Prolia ® in early-stage ER+ breast cancer patients taking an aromatase-inhibitor drug to a placebo arm taking no bone-protecting drug.11,24 They found in the Prolia group:

  • 24% fewer fractures,
  • Reduced bone metastases,
  • Better cancer-free survival,
  • Survival after eight years: 26% Prolia versus 19% placebo, and
  • Few side effects.

The researchers of this unprecedented long-term study cited benefits including the low cost of Prolia generics, injectable dosing of only twice a year, reductions in bone fractures and improved overall survival.

These researchers also commented that while benefits of aromatase inhibitors were long ago established in ER+ (and ER/PR+) patients, the increase in fracture rate, especially in the aging population, sometimes exceeds the reduction in cancer recurrence.

Scientists have noted that another class of drug bisphosphonates are effective in mitigating the bone-damaging effects of anti-estrogen drugs (such as aromatase inhibitors), while improving breast cancer outcomes.

Bisphosphonates have raised more side-effect concerns than Prolia®, but Prolia® can be substituted for bisphosphonates with good results and is well tolerated.30

The downside to Prolia® is that upon cessation, rapid bone loss manifests. This means that once Prolia® is commenced, patients are likely to be on Prolia or another bone-protecting drug for life.12,31 This may be good based on the epidemic of age-related osteoporosis and high fracture rates in the elderly.32 (Prolia patients can also switch to a bisphosphonate if their doctor concurs.33)

Both bone protecting medications (Prolia® or bisphosphonates) are effective at preventing fractures in postmenopausal women with bone loss, and for women with ER+ breast cancer with higher risk of fractures due to treatment.

Those with ER+ breast cancer treated with an aromatase inhibitor should consider speaking to their treating physician about Prolia® or a bisphosphonate to maintain bone density in the face of aggressive estrogen depletion.

A review of prior research comparing Prolia® with bisphosphonates to treat osteoporosis in postmenopausal women found decreased risk of fractures/better bone density with Prolia in four out of six studies reviewed, with no major differences in side effects between the groups.30

Be it Prolia or a bisphosphonate, estrogen-deprived breast cancer patients require bone-protecting drugs to reduce fracture risks, along with skeletal-friendly lifestyles and nutrients.

Reducing Breast Cancer Risks

Lifestyle changes even after breast cancer diagnosis improve odds of achieving a complete response and improve overall survival.34-37

A recent observational study presented evidence that strong collective adherence to cancer-prevention lifestyle recommendations by the American Cancer Society and the American Institute of Cancer Research is associated with significant reductions in disease recurrence and mortality in high-risk breast cancer patients.35

Their most recent recommendations include:35,36

  • Maintain a healthy body weight.
  • Meet the physical activity (PA) guidelines of 150-300 minutes per week of moderate-intensity or 75-150 minutes per week of vigorous-intensity physical activity, and muscle-strengthening activities on two or more days a week.
  • Eat a colorful variety of vegetables and fruits, and plenty of whole grains.
  • Limit red and processed meats, fast food, and other highly processed food.
  • Avoid or limit sugar-sweetened beverages.
  • Avoid or limit alcohol consumption to one drink or fewer per day.
  • Avoid smoking.

Regarding alcohol consumption before and after breast cancer diagnosis, the research is inconsistent, with some studies showing no impact on mortality amongst breast cancer patients.38,39

The easiest decision, however, relates to breast cancer risk reduction strategies.

This includes knowing your risk (i.e. family history), periodic screening (mammogram and clinical breast exam), breast self-exam, and following the American Cancer Society and the American Institute of Cancer Research recommendations.

The following lifestyle recommendations by the American Cancer Society and the American Institute of Cancer Research are associated with significant reductions in disease recurrence and mortality in high-risk breast cancer patients.35

Healthy body Weight

Excercise / physical activity

Varied diet of vegetables, fruits, and whole grains

Limit red meats and other highly-processed foods

Avoid sugar-sweetened beverages

Limit alcohol consumption

Avoid Smoking

The Most Difficult Choices

Upon diagnosis of any type of breast cancer, initial decisions involve lumpectomy or differing degrees of mastectomy, followed by decisions on whole-breast radiation, differing chemo regimens, and other treatments that offer hope, but no assurance of efficacy.

Toxic chemotherapy regimens often induce initial efficacy, but at the cost of side effects that include higher risks of other cancers.

A study published in 2023 found that over a follow-up of 6.2 years, breast cancer survivors had a 70% higher risk of any cancer and a 45% higher risk of non-breast cancer compared with the general population.4

These secondary cancers manifested in the pancreas, colon, lung, skin, and other tissues. Many of these new cancers, such as the three-fold increase in pre-leukemic bone marrow dysplasia correlate with toxic therapies used to fight the initial breast malignancy.

In 2020, an estimated 3.9 million women were living with breast cancer in the United States.1

Thanks to earlier diagnosis and improved treatments many of these 3.9 million women will likely not die from breast cancer.

Many, however, suffer side effects from radiation, hormone ablation, chemo, and other harsh treatments. Women who survive breast cancer but perish years later after drug-induced bone fractures, radiation-induced heart failure or other toxic treatment effects, are too often overlooked when tabulating cancer statistics.

In other words, a woman suffering chemo- and/or radiation-induced heart failure or secondary cancer may not be counted as a breast cancer casualty, even though the fatal disease emanated from prior breast cancer treatments.  

The "difficult choices" title of this editorial relates to the myriad of toxic therapeutics with which a woman stricken with breast cancer is confronted. 

In this month's issue, we reveal recent data sets to provide women with meaningful choices to reduce their odds of contracting breast cancer.

For longer life,

For Longer Life

William Faloon, Co-Founder
Life Extension®


  1. Available at: Accessed 12/12/2023.
  2. Almuwaqqat Z, Meisel JL, Barac A, Parashar S. Breast Cancer and Heart Failure. Heart Fail Clin. 2019 Jan;15(1):65-75.
  3. Lovelace DL, McDaniel LR, Golden D. Long-Term Effects of Breast Cancer Surgery, Treatment, and Survivor Care. J Midwifery Womens Health. 2019 Nov;64(6):713-24.
  4. Ramin C, Veiga LHS, Vo JB, et al. Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort. Breast Cancer Res. 2023 May 3;25(1):50.
  5. Saponaro M, Annunziata L, Turla A, et al. Extended Adjuvant Endocrine Treatment in Luminal Breast Cancers in the Era of Genomic Tests. Int J Mol Sci. 2022 Nov 6;23(21).
  6. Duran-Gomez N, Lopez-Jurado CF, Nadal-Delgado M, et al. Chemotherapy-Related Cognitive Impairment in Patients with Breast Cancer Based on Functional Assessment and NIRS Analysis. J Clin Med. 2022 Apr 23;11(9).
  7. Available at: Accessed May 2, 2024.
  8. Available at: Accessed May 7, 2024.
  9. Early Breast Cancer Trialists' Collaborative G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015Oct 3;386(10001):1341-52.
  10. Gnant M, Fitzal F, Rinnerthaler G, et al. Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. N Engl J Med. 2021Jul 29;385(5):395-405.
  11. Gnant M. Long-term outcomes of adjuvant denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, placebo-controlled ABCSG-18 trial. Paper presented at: American Society of Clinical Oncology Annual Meeting 2022.
  12. Anastasilakis AD, Polyzos SA, Makras P. THERAPY OF ENDOCRINE DISEASE: Denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. Eur J Endocrinol. 2018 Jul;179(1):R31-R45.
  13. Available at: Accessed 12/12/2023.
  14. Han HS, Vikas P, Costa RLB, et al. Early-Stage Triple-Negative Breast Cancer Journey: Beginning, End, and Everything in Between. Am Soc Clin Oncol Educ Book. 2023 Jun;43:e390464.
  15. Available at: Accessed 12/13/2023.
  16. Tapia M, Hernando C, Martinez MT, et al. Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies. Cancers (Basel). 2023 Sep 12;15(18).
  17. Available at: Accessed April 30, 2024.
  18. Trayes KP, Cokenakes SEH. Breast Cancer Treatment. Am Fam Physician. 2021 Aug 1;104(2):171-8.
  19. Available at: Accessed May, 2024.
  20. Gnant M, Frantal S, Pfeiler G, et al. Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer. NEJM Evid. 2022 Dec;1(12):EVIDoa2200162.
  21. Available at: Accessed 12/14/2023.
  22. Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab. 2012 Nov;23(11):576-81.
  23. Cheng C-H, Chen L-R, Chen K-H. Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover. International Journal of Molecular Sciences. 2022;23(3):1376.
  24. Kuhl EA. Adjuvant Denosumab Improves Long-term Survival and Bone Protection in Patients With Early-Stage Breast Cancer Taking Aromatase Inhibitors. ASCO Daily News. 2022.
  25. Sabel MS. Identifying and Managing the High-Risk Patient. Essentials of Breast Surgery: Elsevier; 2009.
  26. Martiniakova M, Mondockova V, Biro R, et al. The link between bone-derived factors osteocalcin, fibroblast growth factor 23, sclerostin, lipocalin 2 and tumor bone metastasis. Front Endocrinol (Lausanne). 2023;14:1113547.
  27. Fessele KL. Bone Health Considerations in Breast Cancer. Semin Oncol Nurs. 2022 Apr;38(2):151273.
  28. Vannala V, Palaian S, Shankar PR. Therapeutic Dimensions of Bisphosphonates: A Clinical Update. Int J Prev Med. 2020;11:166.
  29. Available at: Accessed May 7, 2024.
  30. Chandran T, Venkatachalam I. Efficacy and safety of denosumab compared to bisphosphonates in improving bone strength in postmenopausal osteoporosis: a systematic review. Singapore Med J. 2019 Jul;60(7):364-78.
  31. Anastasilakis AD, Makras P, Yavropoulou MP, et al. Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review. J Clin Med. 2021 Jan 4;10(1).
  32. Sarafrazi N, Wambogo E, Shepherd JA. Osteoporosis or Low Bone Mass in Older Adults: United States, 2017–2018. In: CDC, ed: CDC; 2021.
  33. Mori Y, Izumiyama T, Kurishima H, et al. Effect of denosumab switched from bisphosphonates in preventing joint destruction in postmenopausal rheumatoid arthritis patients with anti-cyclic citrullinated peptide antibodies. J Orthop Surg Res. 2021 Feb 4;16(1):107.
  34. Hamer J, Warner E. Lifestyle modifications for patients with breast cancer to improve prognosis and optimize overall health. CMAJ. 2017 Feb 21;189(7):E268-E74.
  35. Cannioto RA, Attwood KM, Davis EW, et al. Adherence to Cancer Prevention Lifestyle Recommendations Before, During, and 2 Years After Treatment for High-risk Breast Cancer. JAMA Netw Open. 2023 May 1;6(5):e2311673.
  36. Rock CL, Thomson CA, Sullivan KR, et al. American Cancer Society nutrition and physical activity guideline for cancer survivors. CA Cancer J Clin. 2022 May;72(3):230-62.
  37. Sanft T, Harrigan M, McGowan C, et al. Randomized Trial of Exercise and Nutrition on Chemotherapy Completion and Pathologic Complete Response in Women With Breast Cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis Study. J Clin Oncol. 2023 Dec 1;41(34):5285-95.
  38. Lowry SJ, Kapphahn K, Chlebowski R, Li CI. Alcohol Use and Breast Cancer Survival among Participants in the Women's Health Initiative. Cancer Epidemiol Biomarkers Prev. 2016 Aug;25(8):1268-73.
  39. Newcomb PA, Kampman E, Trentham-Dietz A, et al. Alcohol consumption before and after breast cancer diagnosis: associations with survival from breast cancer, cardiovascular disease, and other causes. J Clin Oncol. 2013 Jun 1;31(16):1939-46.