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Breast Cancer

Chapter 07 - Hormonal Anti-Cancer Treatment in the Senior Cancer Patient

In women older than 65 years (and in men with breast cancer), up to 85%of cancers are Oestrogen receptor (ER) and/or progesterone Receptor (PR) positive.

Hormonal agents used commonly are as follows:

  • Selective oestrogen receptor modulator (SERM): tamoxifen
  • Third-generation aromatase inhibitors (AIs): anastrozole and letrozole (nonsteroidal), and exemestane (steroidal)
  • ER downregulator: fulvestrant
  • Progestins: megestrol acetate and medroxyprogesterone

(Neo)adjuvant Hormonal Therapy

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed that five years of adjuvant tamoxifen reduces the annual rate of death from ER+ breast cancer by about 30%, an effect that appears to be independent of age.

Several phase III clinical trials have evaluated the role of AIs given either up front (e.g., ATAC, BIG 1-98) or sequenced/switched after two to three years of tamoxifen (e.g., BIG 1-98, IES, TEAM), and the EBCTCG reported recently the results of a meta-analysis of trials comparing AIs with tamoxifen. The meta-analysis demonstrated improved disease-free survival (DFS) and overall survival (OS) rates for AIs compared with tamoxifen, but the absolute difference in survival is very small for women with low-risk disease.

As a result of a prolonged risk of relapse of hormone receptor positive breast cancer, aromatase inhibitors (e.g., MA.17) and tamoxifen (e.g. ATLAS and aTTom) have been evaluated as ongoing therapy after five years of tamoxifen (extended hormonal therapy). These trials have shown a reduced risk of breast cancer recurrence with prolonged therapy, but again the absolute benefit is small, especially in low-risk patients. In older patients any benefit might be counter-balanced by the risk of death due to the accompanying comorbidities and/or the long-term adverse effects of hormonal therapy.

  • An AI should be used at some point during adjuvant therapy in older women with intermediate- or high-risk breast cancer Five years of treatment with an AI does not give superior survival to a sequenced strategy, which has the advantage of splitting exposure to toxic effects.
  • Up-front use of an AI is the preferred option for postmenopausal women with high-risk breast cancer and in women with contraindications to tamoxifen (e.g., history of thromboembolic disease). There is no basis for continuing AIs beyond five years when used up-front or after switching from tamoxifen.
  • In most women with low to moderate risk breast cancer, five years of tamoxifen remains appropriate. Furthermore, in selected women with a very low-risk ER-positive tumours (e.g. small, low grade, node negative), especially in very old women it may be reasonable to omit adjuvant hormonal therapy.
  • For postmenopausal women with high-risk disease who complete five years of adjuvant tamoxifen, extended treatment with an AI or tamoxifen should be recommended. Unless contraindicated, extended adjuvant AIs are preferred due to an earlier reduction in risk of recurrence compared with extended tamoxifen. There is as yet no information about the role of extending treatment in those who received upfront AI or sequencing strategies, although data from ongoing studies will better determine the optimal duration of endocrine therapy in such patients.

In the neoadjuvant setting, randomised clinical trials (e.g., IMPACT and PO24) showed that AIs lead to higher rates of response and breast conservation and should be considered in older women with locally advanced breast cancer who have hormone receptor – positive breast cancer and in women with contraindications to chemotherapy (Table 1). Although most of the trials investigated neoadjuvant hormonal therapy for 3-4 months only, longer duration of neoadjuvant hormonal therapy can lead to further reduction in tumour size.

Some differences in efficacy between AIs and tamoxifen may be explained by inactivation of or genetic polymorphism in the enzyme Cytochrome P450 (CYP) 2D6, which converts tamoxifen into its active metabolites. However, post-hoc analyses of the BIG 1-98 and ATAC trials found no associations between CYP2D6 Genotype and clinical outcomes and therefore routine testing for genetic Polymorphism of CYP2D6 is not recommended. Use of strong and moderate CYP2D6 inhibitors (e.g., the antidepressants bupropion, fluoxetine or paroxetine) should be discouraged in women who receive tamoxifen; the weak CYP2D6 inhibitors venlafaxine and citalopram are preferred antidepressants in this setting.

Adjuvant therapy with tamoxifen for five years should be recommended to men with early breast cancer. Use of AIs in men has little rationale since 20% of circulating oestrogen is produced in the testicles independently of aromatase (Table below).

Role of Hormonal Therapy in Breast Cancer

StageTherapyIndication
Early breast cancer (adjuvant therapy)Monotherapy with tamoxifen (5 year)
  • Preferred option in older women with low-risk breast cancer (e.g., small tumour size, N-, and HER-2-)
  • Women who cannot tolerate AIs or have relative contraindications for their use
  • Men with early breast cancer
Early breast cancer (adjuvant therapy)Monotherapy with AIs (5 year)
  • An option in women with high-risk breast cancer (e.g., large tumour size, N+, or HER-2+)
  • Women who cannot tolerate tamoxifen or have contraindications for its use
Early breast cancer (adjuvant therapy)Sequenced hormonal therapy (AI 2-3 years after initial use of tamoxifen for 2-3 years, or vice-versa in total for 5 years)
  • Women with moderate/high risk breast cancer, in whom AI was not used up-front
Early breast cancer (adjuvant therapy)Extended hormonal therapy with AI or tamoxifen –after 5 years of tamoxifen)
  • Women with high-risk breast cancer (e.g., N+ disease)
Early breast cancer (adjuvant therapy)Neoadjuvant hormonal therapy with AIs/tamoxifen (3-4 months or preferably longer if response)
  • Women with strongly endocrine-responsive locally advanced breast cancer, especially important for senior women
  • Women with endocrine-responsive breast cancer, in whom chemotherapy is not possible because of contraindications
Advanced breast cancerTamoxifen, non-steroid AIs, steroid AIs, fulvestrant, progestins
  • Sequential administration of available hormonal agents due to incomplete cross-resistance (not appropriate for women who have endocrine-resistant disease (as per ABC2 guidelines)

Abbreviations: AI, aromatase inhibitors; N, lymph node.

Hormonal Therapy in Advanced Breast Cancer

Hormonal therapy is the treatment of choice for older women with meta- static hormone receptor – positive tumours with metastases predominantly to bone and soft tissues and/or with asymptomatic slowly progressive visceral disease. Women with endocrine-responsive breast cancer may benefit from sequential administration of hormonal agents because of incomplete cross-resistance between them: tamoxifen, AIs, fulvestrant and progestins can lead to tumour response and relief of symptoms.

In randomised clinical trials, AIs demonstrated better response rates and progression-free survival (but not overall survival) as compared with tamoxifen or megestrol acetate. The addition of the mTOR inhibitor everolimus to the steroidal AI exemestane has been shown to significantly prolong progression-free survival (PFS), but does not improve overall survival. Everolimus substantially increases toxicity with almost 1 in 4 patients discontinuing the drug, so this strategy has questionable therapeutic benefit. After second-line hormonal treatment, there is no high-level evidence to assist in selecting the optimal agent. When fulvestrant is used after previous hormonal therapies, ~30% of women derive clinical benefit. According to the results of a meta-analysis, use of high dose fulvestrant monotherapy in first line or in patients with limited prior exposure to adjuvant endocrine therapy may delay progression compared with an AI. A recent study showed substantial improvement in PFS when fulvestrant was combined with the cycle-dependent kinase inhibitor palbociclib, which is well tolerated, but data are too immature to accurately evaluate overall survival.

Women diagnosed with metastatic endocrine-responsive breast cancer who did not receive adjuvant hormonal therapy or had a long disease-free interval after such therapy have a high chance of response to hormonal therapy at the time of recurrence. In contrast, women recurring during adjuvant hormonal therapy have a lower probability of response to further hormonal manipulations.

Although not recommended in the adjuvant setting in male patients, AIs can cause protracted stability and objective responses in some men with advanced breast cancer.

False negative determinations of ER and PR status may occur. Thus, hormonal therapy may be active in some women who were reported to have ER-negative and PR-negative tumours, especially in soft tissue and/or bone predominant disease. Further, differences in hormonal status between primary and metastatic sites are reported, and biopsy for determination of hormonal status should be encouraged at time of recurrence.

Side Effects of Hormonal Therapy in Breast Cancer

Major side effects of tamoxifen, AIs, and other hormonal agents used in the treatment of breast cancer are summarised in the Table below. Tamoxifen increases the risk of rare adverse events such as uterine cancer (including uterine sarcoma) and thromboembolic disease, and elderly women are at higher risk to develop these toxicities. Women receiving an AI have a lower risk of uterine cancer and thromboembolic events compared with women on tamoxifen but a higher likelihood of developing arthralgias, fractures, urogenital atrophy and ischaemic cardiac events. Bone loss and fractures are of particular concern in older patients, especially those with pre-existing osteopenia or osteoporosis: all women receiving an AI should be encouraged to exercise and given calcium and vitamin D supplementation; their bone density should be assessed annually, with a bisphosphonate or denosumab prescribed if bone loss is documented. Randomised data show similar frequency of cerebrovascular disease between AIs and tamoxifen. Observational data suggest that the prevalence of AI-related joint symptoms is higher than reported in phase III clinical trials. In unselected patients, fulvestrant monotherapy is associated with similar efficacy, but reduced arthralgia compared with other endocrine therapy options. Side effects can be an important cause of noncompliance with treatment and should therefore be actively sought and addressed during treatment with hormonal therapy.

Major Side Effects of Hormonal Therapy in Breast Cancer

TherapyMajor Side Effects
Tamoxifen
  • Hot flashes
  • Venous thromboembolism, stroke
  • Vaginal discharge, uterine hyperplasia/polyps endometrial cancer
  • Fluid retention, muscle cramps
  • Cataract, retinopathy
  • Increased triglycerides (but favourable effect on cholesterol)
  • Other (tumour flare, Alopecia, gastrointestinal intolerance, headache)
Aromatase inhibitors
  • Hot flashes
  • Vaginal dryness/atrophy
  • Joint pain/stiffness, muscular pain, carpal tunnel syndrome,
  • Bone loss/fracture
  • Ischemic heart disease
  • Other (gastrointestinal intolerance, alopecia, headache, rash, elevated LFT)
Fulvestrant
  • Hot flashes (mild)
  • Gastrointestinal disturbance (mild): elevated LFT
  • Injection site reaction
  • Other (headache, rash, UTI)
Progestins
  • Increased appetite, weight gain
  • Gastrointestinal disturbance
  • Hot flashes
  • Venous thromboembolism
  • Other (tumour flare, rash, gynaecomastia, pituitary axis abnormalities)

Abbreviations: LFT, liver function tests

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