The Risk Of Late Recurrence
Hormone receptor-positive breast cancers are characterized by a risk of late recurrence for years. Recurrences occur at a steady rate throughout the period from 5 to 20 years, strongly correlated with the original tumor and nodal status and the tumor grade. At least 50% of recurrences occur more than 5 years after diagnosis. The long-term risk of recurrence is about 12% per year. Estimating the risk of recurrence accurately is important because if the risk is low, even the most effective adjuvant therapy can only result in limited overall improvement. In an analysis by Pan et al. , after 5 years of ET for patients with stage T1 disease the risk of distant recurrence in the period from 5 to 20 years was 13% for N0, 20% with N13 status, and 34% with N49 status. Among T2 tumors, the risks were 19, 26, and 41%, respectively. Considering the impact of grade among patients with T1 N0 disease, the risk of distant recurrence was 10% for low-grade and 17% for high-grade disease. An EBCTCG analysis on this question presented by Pan et al. showed an improved outcome for patients after only 5 years of ET diagnosed after the year 2000 in comparison with diagnosis of breast cancer before the year 2000. Possible explanations for the 25% reduction of distant recurrences in years 59 are the detection of lower-risk lesions by early detection and screening, an improved compliance to treatment and treatment guidelines, and real treatment improvements.
Hormone Therapy For Breast Cancer
Some types of breast cancer are affected by hormones, like estrogen and progesterone. The breast cancer cells have receptors that attach to estrogen and progesterone, which helps them grow. Treatments that stop these hormones from attaching to these receptors are called hormone or endocrine therapy.
Hormone therapy can reach cancer cells almost anywhere in the body and not just in the breast. It’s recommended for women with tumors that are hormone receptor-positive. It does not help women whose tumors don’t have hormone receptors.
How Can Hormones Affect The Growth Of Breast Cancer
Hormones like estrogen and progesterone are chemicals produced by glands in the body. Normally, these hormones help regulate body cycles, like menstruation. However, sometimes these same hormones can cause cancer to grow.
The pathologist will perform tests on the breast cancer cells to determine if they have receptors that feed on estrogen or progesterone, stimulating their growth. If the cancer cells have these receptors, your doctor may recommend hormone therapy drugs, such as blockers or inhibitors. Both types of drugs help to destroy cancer cells by cutting off their supply of hormones.
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Are There Risks To Taking Tamoxifen
Yes. The risks include:
- Fertility. Tamoxifen can increase your fertility for a short time. But it might harm a growing baby, so itâs important to use some form of barrier birth control while youâre taking it, like condoms or a diaphragm. Donât use birth control pills. They can change how the drug works and affect the breast cancer. Tell your doctor right away if you think youâve become pregnant while youâre taking tamoxifen.
- Blood clots. Women who take tamoxifen may have a slightly higher risk of blood clots in their lungs or large veins. Itâs an even bigger risk for smokers.
- Uterine cancer or sarcoma. The drug may make a woman more likely to get these diseases. But this risk is small, and it may be outweighed by the benefits of tamoxifen for breast cancer treatment. Talk to your doctor to know for sure.
- Cataracts. Tamoxifen seems to give some women a higher chance of having this condition, which clouds the lens inside the eye. People have also reported eye problems such as corneal scarring or retinal changes.
- Medications. Tamoxifen may affect how other drugs work in your body.
Hormonal Therapy: What To Expect
There are three different types of hormonal therapy medicines:
- aromatase inhibitors:
Hormonal therapy is used to treat any stage of hormone-receptor-positive breast cancer or to reduce the risk of developing it or having a recurrence. Hormonal therapy can be used by both pre- and postmenopausal women. Hormonal therapy can be given before, at the same time as, or after other breast cancer treatments.
Besides treating hormone-receptor-positive breast cancers, hormonal therapy medicines also can be used to:
- lower the risk of hormone-receptor-positive breast cancer coming back
- lower the risk of hormone-receptor-positive breast cancer in women who are at high risk but haven’t been diagnosed with breast cancer
Because there are seven different hormonal therapy medicines and because people take hormonal therapy for many different reasons, your hormonal therapy regimen will depend on your unique situation. Some of the most common situations are discussed below.
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Ovarian Suppression Or Ablation
For premenopausal women with estrogen receptor-positive breast tumors, ovarian ablation or suppression may be an option. Since a premenopausal womans ovaries are the main source of estrogen production, temporarily or permanently shutting off their function has been shown to be effective in reducing the chances of a breast cancer recurrence. Studies are now confirming their usefulness when given with tamoxifen instead of chemotherapy or after chemotherapy. This is called ovarian ablation or suppression and can be done through surgery or monthly hormonal injections . The injection of medication will prevent you from ovulating or menstruating and will put you in temporary menopause. Surgery will prevent you from having to undergo monthly injections, but will put you in irreversible menopause. You should speak to your doctor regarding any plans to conceive children so that together you can decide which option is best for you and your family.
Early Versus Delayed Treatment
For men who need hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who dont yet have symptoms, its not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if its started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.
But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldnt be started until a man has symptoms from the cancer. This issue is being studied.
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Treatment Of Breast Cancer Stages I
The stage of your breast cancer is an important factor in making decisions about your treatment.
Most women with breast cancer in stages I, II, or III are treated with surgery, often followed by radiation therapy. Many women also get some kind of drug therapy. In general, the more the breast cancer has spread, the more treatment you will likely need. But your treatment options are affected by your personal preferences and other information about your breast cancer, such as:
- If the cancer cells contain hormone receptors. That is, if the cancer is estrogen receptor -positive or progesterone receptor -positive.
- If the cancer cells have large amounts of the HER2 protein
- How fast the cancer is growing
- Your overall health
- If you have gone through menopause or not
Talk with your doctor about how these factors can affect your treatment options.
Side Effects Her2 Targeted Therapy Drugs
The side effects of HER2 targeted drugs are often mild, but some can be serious. Discuss what you can expect with your doctor.
The monoclonal antibodies and antibody-drug conjugates can sometimes cause heart damage during or after treatment. This can lead to congestive heart failure. For most women, this effect lasts a short time and gets better when the drug is stopped. The risk of heart problems is higher when these drugs are given with certain chemo drugs that also can cause heart damage, such as doxorubicin and epirubicin . Because these drugs can cause heart damage, doctors often check your heart function before treatment, and regularly while you are taking the drug. Let your doctor know if you develop symptoms such as shortness of breath, leg swelling, and severe fatigue.
Lapatinib, neratinib, tucatinib, and the combination of pertuzumab with trastuzumab can cause severe diarrhea, so its very important to let your health care team know about any changes in bowel habits as soon as they happen.
Lapatinib and tucatinib can also cause hand-foot syndrome, in which the hands and feet become sore and red, and may blister and peel.
Fam-trastuzumab deruxtecan can cause serious lung disease in some women. In some cases this might even be life threatening. Its very important to let your doctor or nurse know right away if youre having symptoms such as coughing, wheezing, trouble breathing, or fever.
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The Effects Of Inhibiting Pi3k
PI3K-AKT-mTOR signaling is the most common aberrantly activated pathway in ER+BC, and this aberrant signaling has been acknowledged as the main cause of endocrine resistance . Various targeted drugs for inhibiting this pathway have been developed to reverse endocrine resistance and have shown promising results . In addition to staving tumor growth, inhibitors of this pathway also impact the functions of multiple immune cells . Therefore, the effects of these therapeutic strategies on the TIM deserve attention.
The Effects Of Cdk4/6 Inhibitors On The Immune Microenvironment
The cyclin D/cyclin-dependent kinases 4 and 6 -retinoblastoma protein pathway holds a core position in the development of BC. CDK4/6 inhibitors , including abemaciclib, palbociclib and ribociclib, in combination with hormone therapy have been used to treat hormone receptor-positive , HER2-negative metastatic BC . In addition to inducing tumor cell cycl e arrest, mounting evidence reveals the immune modulatory of CDK4/6i in the TIM of BC .
CDK4/6i enhance the immunogenicity of BC cells through a variety of mechanisms. Abemaciclib and palbociclib boosted the production of type III IFNs of BC cells by abolishing the action of RB-E2F-DNMT1 axis, which further drove the expression of IFN-stimulated genes in an autocrine manner and enhanced tumor antigen presentation . Abemaciclib monotherapy also upregulated the expression of MHC class I and II in tumor cells in favor of immune-mediated tumor clearance .
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Can Other Drugs Interfere With Hormone Therapy
Certain drugs, including several commonly prescribed antidepressants , inhibit an enzyme called CYP2D6. This enzyme plays a critical role in the body’s use of tamoxifen because CYP2D6 metabolizes, or breaks down, tamoxifen into molecules, or metabolites, that are much more active than tamoxifen itself.
The possibility that SSRIs might, by inhibiting CYP2D6, slow the metabolism of tamoxifen and reduce its effectiveness is a concern given that as many as one-fourth of breast cancer patients experience clinical depression and may be treated with SSRIs. In addition, SSRIs are sometimes used to treat hot flashes caused by hormone therapy.
Many experts suggest that patients who are taking antidepressants along with tamoxifen should discuss treatment options with their doctors, such as switching from an SSRI that is a potent inhibitor of CYP2D6, such as paroxetine hydrochloride , to one that is a weaker inhibitor, such as sertraline or citalopram , or to an antidepressant that does not inhibit CYP2D6, such as venlafaxine . Or doctors may suggest that their postmenopausal patients take an aromatase inhibitor instead of tamoxifen.
Other medications that inhibit CYP2D6 include the following:
- Quinidine, which is used to treat abnormal heart rhythms
Regulators Of Gene Expression
Razavi et al. found enrichment of alterations in the transcriptional regulators MYC, FOXA1, CTCF, and TBX3 in endocrine-resistant MBCs. These were mutually exclusive with alterations in ESR1 or MAPK pathway components. Alterations in MYC, FOXA1, and CTCF were found to be either pre-existing or acquired following endocrine therapy . A Myc activation signature was previously associated with endocrine resistance in long-term estrogen-deprived cells and poor response to tamoxifen in patients . CTCF is a transcriptional repressor of Myc , suggesting CTCF loss-of-function mutations may lead to Myc upregulation. Decreasing Myc expression with BET inhibitors may be a potential strategy to overcome resistance in tumors with MYC or CTCF alterations . Recent studies have demonstrated that direct targeting of Myc may also be possible . FOXA1 is a pioneering factor involved in chromatin remodeling and has been shown to cooperate with ER to induce gene expression . Thus, tumors with FOXA1 mutations may still rely on ER protein expression and hence remain sensitive to SERDs. However, promoter hotspot mutations in FOXA1 that increased FOXA1 expression were associated with reduced sensitivity to fulvestrant .
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The Effects Of Serms And Serds On The Tumor Immune Microenvironment
SERMs and SERDs are currently the most important endocrine therapeutic regimens for BC. SERMs, represented by tamoxifen, toremifene and raloxifene, work through competitive blockage of the interaction between estrogen and ER. SERDs, such as fulvestrant, contribute to the downregulation and degradation of ER . Accumulating evidence from experimental and clinical studies has revealed the multifaceted immunomodulatory effects of SERMs and SERDs in particular, progress has been made to elaborate how SERMs and SERDs act upon the immune microenvironment of BC .
Table 1 The effects of different endocrine therapeutic strategies on immune cells
In addition to being effective for treating BC, tamoxifen and raloxifene have also been shown to reduce the risk of BC in highly susceptible women . Tamoxifen administration was found to upregulate IFN-related genes in normal human mammary epithelial cells from in vitro experiments, implying its positive effect on the immune surveillance of normal breast tissue . Moreover, tamoxifen and toremifene were also found to enhance TNF-R2 expression on activated T cells by inhibiting the activation of JNK and promoting TNF-R2-mediated T cell proliferation . These results might explain their BC-preventive effect.
Ai In Women With Chemotherapy
Chemotherapy-induced ovarian failure must not guide a treatment decision in the direction of an AI even after 23 years of tamoxifen. van Hellemond et al. reported an analysis of endocrine data of 329 DATA study participants with COF. In the DATA study all patients had taken tamoxifen prior to anastrozole for 23 years. These patients had a median age of 50 years . Thirty-nine patients developed ovarian function recovery under treatment with AI. Of these, 11 were aged 50 years or older at AI initiation. The estradiol level decreased statistically significantly for all women under AI treatment. However, the estradiol levels in the women who experienced OFR remained higher prior to OFR diagnosis compared with those who did not experience OFR. The 30-month OFR was 5.1% for patients aged 50 years or older vs. 25.2% for patients younger than 50 years. The results are in line with earlier smaller studies which described OFR rates of about 30% under treatment with AI in women with COF.
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Ovarian Ablation Or Suppression
For women who havent gone through menopause, ovarian ablation may be an option. This can be done medically or surgically. Either method stops estrogen production, which inhibits growth of cancer.
Surgical ablation is done by removing the ovaries. Without production of estrogen from the ovaries, you will enter permanent menopause.
Targeted Therapy For Her2
In about 1 in 5 women with breast cancer, the cancer cells have too much of a growth-promoting protein known as HER2 on their surface. These cancers, known as HER2-positive breastcancers, tend to grow and spread more aggressively. Different types of drugs have been developed that target the HER2 protein.
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Alterations In Er And Aromatase
While the LBD mutations reduce the potency of fulvestrant , next-generation oral SERMs or SERDs that target both WT and mutant ER are in clinical development . For example, GDC-9545 and elacestrant are oral SERDs that have shown preliminary clinical activity in ESR1-mutant MBCs, some of which had progressed on prior SERDs these agents demonstrated acceptable toxicity profiles . Similarly, the oral SERD AZD9496 reduced on-treatment ESR1-mutant ctDNA levels and GDC-0810 reduced 18F-fluoroestradiol uptake by positron emission tomography in patients with ESR1 mutations . The selective estrogen receptor covalent antagonist H3B-6545 covalently binds the Cys530 residue of both WT and mutant ER, enforcing an irreversible antagonist conformation .
Role Of Histone Deacytelase Inhibitors
DNA usually winds around histones, whose modification may lead to alterations in DNA structure, which may in turn affect transcription. In general, histone acetylation is associated with chromatin relaxation while deacetylation leads to chromatin condensation, creating a structure called heterochromatin where transcription is repressed. Because of their ability to affect DNA structure, histone deacytylase inhibitors are expected to have a potent role in cancer pathogenesis and progression.
HDAC1 is a prototypical deacetylase that is expressed in many tumor types, including breast cancer. Overexpression of HDAC1 in breast cancer cell line models affects ERÎ± gene expression, leading to suppression of ERÎ± protein.
Several trials have assessed the role of histone deacetylase inhibitors such as entinostat in the treatment of HR-positive ABC, especially as a means to overcome resistance to endocrine therapy .
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Cdk4/6 Inhibition In Early
The exciting results observed with CDK4/6 inhibitors in the treatment of advanced ER-positive, HER2-negative breast cancer have triggered the evaluation of these agents in the early-stage setting. For example, results of a neoadjuvant therapy setting were presented by Dowsett et al. from the PALLET study. In this study, palbociclib was given in addition to 3 months of the AI letrozole. It was shown that the antiproliferative effect of the AI is substantially increased by palbociclib. The percentage of tumors which underwent a complete cell cycle arrest in the form of a Ki-67 value < 2.7% during neoadjuvant therapy was able to be increased through the addition of palbociclib from 58.5 to 90.4%. In the adjuvant setting the PALLAS study has included 4,600 patients with stage II and III breast cancer and randomized between standard endocrine treatment +/ palbociclib. Comparable study concepts exist for abemaciclib and ribociclib .
The ADAPTcycle study follows a different approach: the comparison of ET plus ribociclib versus standard chemotherapy in intermediate-risk ER+/HER2 early breast cancer.
Results are eagerly awaited to establish new treatment options for early luminal B breast cancers.