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 to not 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 osteoporosis compared to the five additional years’ treatment arm.

The bone fracture 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.

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,

William Faloon, Co-Founder, Life Extension®

References

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