Hormone Breast Cancer Treatments: Section 8.b.

CONTENTS:

8.5 Hormone Therapy for Breast Cancer
8.5.1 Ovarian Ablation
8.5.2 Tamoxifen
8.5.3 Aromatase Inhibitors – Exemestane (Aromasin®)
8.6 ‘Targeted’ Therapy for Breast Cancer
8.6.1 Trastuzumab (Herceptin®)
8.6.2 Pertuzumab (Perjeta®)
8.6.3 Ado-Trastuzumab Emtansine (Kadcyla®)
8.6.4 Cetuximab (Erbitux®)

Breast cancer treatments can be tough but be clothed in strength, dignity and a little laughter whenever you can.

8.6.5 Bevacizumab (Avastin®)
8.6.6 Lapatinib (Tykerb®)
8.6.7 PARP Inhibitors – olaparib (Lynparza®)
8.6.8 mTOR Inhibitors – everolimus (Afinitor®)
8.7 Treatment for Carcinoma In-Situ
8.7.1 Surgical Excision for DCIS
8.7.2 Post-Excision Radiotherapy for DCIS
8.7.3 Multigene Analysis for Recurrence of DCIS
8.7.4 Systemic Treatment for DCIS
8.7.5 Recurrence Rate for DCIS Following Excision

This page is section 8B in breast cancer treatments. Back to 8A Treatment for Breast Cancer. Forward to 8C Treatment for Stage of Breast Cancer

8.5 Breast Cancer Treatments: Hormone Therapy

Certain glands in the body produce hormones and provide growth stimuli to other tissues. In the main, the ovaries produce Estrogen and progesterone.

Hormone therapy (‘hormonal therapy,’ ‘endocrine therapy’ or ‘hormone treatment’) for breast cancer includes compounds that block hormone receptors, add synthetic hormones or remove hormones.

Hormones are unpleasant chemicals. They mess up my week once a month!

Hormones also allow women to know the exact difference between beige, cream, off-white and eggshell.

Oh yes, they also help us to understand the facial expressions of cats.

Some, but not all, breast cancer is hormone-dependent. A breast cancer specialist can determine if a breast cancer is hormone-dependent by the detection of estrogen receptor (ER) and progesterone receptor (PR) expression by the tumor cells. Estrogen (ER) and/or progesterone (PR) receptor-positive breast cancers account for 75 % of all breast cancers.

Hormone therapy is a breast cancer treatment for hormone positive breast cancers. Your breast cancer specialist will usually give hormonal therapy in combination and as adjuvant therapy.

What is adjuvant therapy again?

Adjuvant therapy is cancer treatment that is given as well as the main treatment to lower the risk of the cancer coming back or spreading.

8.5.1 Ovarian Ablation

Although an uncommon procedure, removal of the ovaries will limit the growth of estrogen-dependent breast cancer.

8.5.2 Breast Cancer Treatments: Tamoxifen

Tamoxifen is an estrogen analog that blocks the tumor receptors for naturally produced estrogen. Tamoxifen is used in the treatment of ER-positive early-stage and metastatic breast cancer.

The use of tamoxifen does increase the risk of endometrial (uterine) hyperplasia and cancer, so specialists advise that women taking tamoxifen should have a pelvic examination every year.

8.5.3 Aromatase Inhibitors – Exemestane (Aromasin®)

Aromatase is an enzyme that converts androgen to estrogen. Aromatase inhibitors block the enzyme aromatase. 2Q8A0335 Aromatase inhibitors are used to treat post-menopausal women who have hormone-dependent breast cancer.

Aromatase inhibitors are not in use as a single-agent therapy in women with intact ovarian function. Your breast cancer specialist may prescribe Aromatase inhibitors instead of tamoxifen in early-stage breast cancer. Furthermore, clinical trials are assessing the use of Aromatase inhibitors for a possible role in the treatment of metastatic breast cancer.

I’m great in bed. I can sleep for days.

8.6 ‘Targeted’ Therapy: Breast Cancer Treatment

Targeted therapy is a breast cancer treatment that uses drugs or antibodies to block or remove particular factors that the cancer cells express. Indeed, some cancers needs these factors to grow or spread. Targeted therapy may also treat the tumor by removing its blood supply or preventing the spread of the tumor.

These breast cancer treatments that specifically target the tumor, actually leaves normal cells alone.

Now that is very clever, drugs that only act on the cancer cells.

Yes, these drugs also have less severe side effects which is good news all round.

Did somebody say ‘good news’ and ’round’ in the same sentence, that says pancakes to me!

This area of breast cancer treatments have been developing rapidly over the past ten years. At present, targeted therapy in breast cancer is of four main types:-

Monoclonal antibody therapy
Tyrosine kinase inhibitors (TKI)
PARP inhibitors (used for Triple Negative Breast Cancer)
mTOR inhibitors

8.6.1 Trastuzumab (Herceptin®)

Monoclonal antibody breast cancer treatment uses highly specific antibodies. Themonoclonal antibodies can localize to a single specific site on or in a cell. Breast cancer physicians use monoclonal antibodies as combination therapy with chemotherapy or as adjuvant therapy.

Trastuzumab (Herceptin®) is the best-known monoclonal antibody for use in breast cancer treatment. This drug can treat HER2-positive, early-stage breast cancer following surgery and chemotherapy. Also, medics will use Trastuzumab (Herceptin®) in combination with chemotherapy and hormone therapy to treat advanced metastatic breast cancer.

What is HER2

HER2 or Human Epidermal Growth Factor Receptor 2 is a protein, caused by a gene mutation, that is found in cancer cells and promotes growth.

This monoclonal antibody blocks the effects of HER2 which is a growth factor for breast cancer. Between 20 % and 25 % of patients have breast cancer that responds well to trastuzumab (Herceptin®) in combination with chemotherapy (Moja et al., 2012).

A clinical trial, Herceptin Adjuvant (HERA), of 2013 analyzed the clinical response in more than 5,000 women with HER2-positive breast cancer. The trial shows that 2 years of adjuvant trastuzumab (Herceptin®) therapy was no more effective than 1 year of adjuvant trastuzumab (Herceptin®) therapy for patients with HER2-positive, early breast cancer (Goldhirsch et al., 2013).

Now I’m totally lost, I have a ‘deja-vu’ feeling of sitting in algebra at school.

It’s not difficult, simply speaking drug trials show that continuing the drug (trastuzumab or Herceptin®) for two years is no better than taking it for one year in early-stage breast cancers.

8.6.2 Pertuzumab (Perjeta®)

Pertuzumab (Perjeta®) is a monoclonal antibody that may be combined with trastuzumab (Herceptin®) and chemotherapy to treat breast cancer. Pertuzumab (Perjeta®) may be used to treat a sub-set of breast cancer patients with HER2-positive tumors that have metastasized.

Pertuzumab (Perjeta®) may also be used as neo-adjuvant therapy in patients with early-stage HER2-positive breast cancer.

So, very simply then, Perjeta® can be used in both early stage breast cancers and those that have spread, or metastasized.

8.6.3 Ado-Trastuzumab Emtansine (Kadcyla®) (T-DM1)

Ado-Trastuzumab Emtansine (Kadcyla®) is a monoclonal antibody that is linked to an anticancer drug (DM1); this compound is called an ‘antibody-drug conjugate.’

Do these drugs have a lot of side effects?

Different drug therapies will have different side effects, but every patient will react differently.

You just have to focus on what those drugs are doing to the cancer.

The most common side effects for Kadcyla, for example, are fatigue, nausea, musculoskeletal pain, headache, and constipation.

Ado-Trastuzumab Emtansine (Kadcyla®) is used to treat HER2-positive, metastatic breast cancer in patients who have already received treatment with a taxane and trastuzumab (Herceptin®). It may also be used in patients whose cancer has recurred after adjuvant therapy with these drugs.

8.6.4 Cetuximab (Erbitux®)

breast cancer treatment The monoclonal antibody, cetuximab (Erbitux®) is monoclonal antibody to the epidermal growth factor receptor (EGFR).

Many triple negative breast cancers (TNBC) have been found to ‘over-express’ EGFR. This receptor, EGFR, receives cell signals that stimulate the cancer cell to grow; the monoclonal antibody cetuximab (Erbitux®) attaches to EGFR, blocks the signals and prevents the cancer cells from growing.

8.6.5 Bevacizumab (Avastin®)

As cancer cells divide and the tumor increases in size, ‘angiogenesis’ factors produced by the tumor, such as vascular endothelial growth factor (VEGF) stimulate new vessel formation.

Bevacizumab (Avastin®) is a monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A). Bevacizumab (Avastin®) was the first anti-angiogenic targeted therapy to be evaluated in breast cancer

In 2007, in the E2100 Study, Miller and colleagues compared the efficacy and safety of paclitaxel (Taxol®) alone, with that of paclitaxel (Taxol®) plus bevacizumab (Avastin®) in an open-label, randomized, phase 3 trial, as initial treatment for metastatic breast cancer (Miller et al., 2007). The findings were that initial therapy of metastatic breast cancer with paclitaxel (Taxol®) plus bevacizumab (Avastin®) prolonged progression-free survival (PFS), but not overall survival (OS), as compared with paclitaxel alone.

In 2008, bevacizumab (Avastin®) received approval for the treatment of metastatic breast cancer by the US Food and Drug Administration (FDA). But in 2010, new studies from clinical trials were presented to the FDA that did not support benefit for women receiving bevacizumab (Avastin®) as a part of their treatment. In 2011, the FDA withdrew the breast cancer ‘indication’ for bevacizumab (Avastin®).

Oh, all this medication information is quite overwhelming. What on earth does ‘indication’ mean here?

Well if you take away the indicators you can’t signal left or right, of course.

In the case of medical drugs an ‘indication’ is a valid reason to use a certain medication. You will have seen a leaflet that comes with your medication saying ‘indication and usage’. Indications are strictly regulated according to the drug’s efficacy and safety

Angiogenesis as a target for therapy in breast cancer continues to be studied. Another monoclonal antibody that targets VEGF is sutinib (Sutent®).

8.6.6 Lapatinib (Tykerb®)

Lapatinib (Tykerb®) is a tyrosine kinase inhibitor (TKI) that targets the HER2 protein and other growth promoting proteins inside the breast cancer cell.

In addition, Lapatinib (Tykerb®) is used as part of combined therapy in patients with HER2-positive breast cancer that has progressed after trastuzumab (Herceptin®) treatment.

8.6.7 PARP Inhibitors – olaparib (Lynparza®)

The enzyme, poly ADP ribose polymerase (PARP), is used by cells to repair DNA damage. Inhibitors of PARP block DNA repair and may cause rapidly dividing cells, such as cancer cells, to die.

PARP inhibitors have been designed to target cancer in patients carrying inherited mutations in the BRCA1 or BRCA2 genes; they have been studied in clinical trials for patients with cancers of the breast, ovary and prostate that are associated with these gene mutations (Farmer et al., 2005).

PARP inhibitor therapy is also being investigated for the treatment of triple-negative breast cancer (TNBC).

Clinical trials of PARP inhibitors in breast cancer have shown some disappointing results so far. One PARP inhibitor, olaparib (Lynparza®), has shown some benefit when used in combination with chemotherapy for triple-negative breast cancer (TNBC).

8.6.8 mTOR Inhibitors – everolimus (Afinitor®)

mTOR is a protein or growth factor that promotes cell division and possibly angiogenesis. Everolimus (Afinitor®) blocks mTOR and is a treatment that can be taken in tablet form once a day.

What is angiogenesis again? I’m so sorry I keep forgetting things.

Angiogenesis is when new blood vessels form; tumours need these blood vessels to grow and spread, so the drug Everolimus works as a type of ‘blocker’ to this process.

I’m never going to pass the test on all these drugs!

How many times? There is NO test!

Everolimus (Afinitor®) is approved by the FDA to treat advanced, HER2-negative, hormone receptor-positive breast cancer in post-menopausal women in combination with paclitaxel (Taxol®).

8.7 Breast Cancer Treatments for Carcinoma In-Situ

The 2010 American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) gives carcinoma in-situ the designation of Tis and Stage O (Tis, No, Mo).

Stage 0, is that bad news?

Stage 0 simply means that cancer has been found ‘in situ’ or is ‘in place’. It is the earliest stage of cancer.

Well that must be a bit of a mixed bag. Shock to find out you have cancer and maybe a bit of relief that it has been found so early.

Lobular carcinoma in-situ (LCIS) is not usually detected by screening mammography but is found incidentally on histology of biopsies or resection specimens. LCIS has been shown to progress to invasive lobular carcinoma (ILC) in up to 15% of cases. Patients with LCIS are offered one of three options

Life-long surveillance with the goal of detecting subsequent malignancy at an early stage;
chemo-prevention
bilateral prophylactic mastectomy.

However, trends in the management of LCIS have moved toward more conservative management. The treatment for LCIS remains controversial, and there are, as yet, no proven benefits of surgery or radiotherapy (Oppong & King, 2011).

For ductal carcinoma of the breast, the AJCC staging classification is Tis (DCIS)

Treatment of DCIS is done to prevent invasive cancer. ‘Extensive DCIS’ occupies several ducts and quadrants of the breast; when found at several areas throughout the breast, it is known as ‘multi-centric DCIS.’ For women with this presentation of DCIS, their physician may recommend a mastectomy instead of a lumpectomy.

The treatment options for DCIS may be summarized:-

8.7.1 Breast Cancer Treatments: Surgical Excision for DCIS

The results of the ECOG 5194 study (Hughes et al., 2009) suggest that a local excision alone may be sufficient treatment for patients with low- to intermediate-grade DCIS. Sentinel lymph node dissection (SLND) is not indicated in the evaluation of patients undergoing breast-conserving management of DCIS. In DCIS, the axillary lymph nodes are rarely involved, even with extensive multifocal, high-grade disease.

If you’re a lady who is facing, or has already had, breast surgery remember that scars are tattoos with better stories.

Sometimes, sampling of the axillary nodes by Sentinel Lymph Node biopsy is indicated for patients undergoing mastectomy because occult invasive breast cancer may be identified at surgery, and SLND is not feasible after mastectomy

8.7.2 Post-Excision Radiotherapy for DCIS

For patients with high-grade DCIS, post-excision radiotherapy may be an important treatment for reducing the risk of breast disease in the same breast.

Radiotherapy, that word is scary. It’s the thought of losing your hair and being very sick.

You don’t lose your hair from radiation, it doesn’t give you nausea, and it is pain free. It’s a fantastic treatment, except for being boring.

Boring and it messes up your routine daily schedule for a few weeks, being at the treatment clinic instead of at work or on vacation.

I need a rest after vacations anyway.

Selection of patients for excision alone is not easy, but gene expression analysis may help to select such patients. At this time, there are no clinico-pathologic features of DCIS that reliably predict whether wide local excision, with or without radiotherapy, would be most beneficial.

8.7.3 Multigene Analysis for Recurrence of DCIS

The ECOG trial utilized a ‘DCIS Recurrence Score’ which was a multi-gene assay (Hughes et al., 2009). In preliminary analysis, patients were stratified by recurrence score into three groups that were associated with a risk of DCIS or invasive breast cancer.

Although such a DCIS scoring system may help select patients who should undergo adjuvant radiation, further studies to validate these results are required before the multigene assay can become part of clinical assessment.

8.7.4 Breast Cancer Treatments: Systemic Treatment for DCIS

The risk of distant metastases in women with DCIS is very low, and the clinical prognosis is excellent. Chemotherapy plays no role in the clinical management of DCIS.

Low risk of spread, no chemo and an excellent prognosis – now that is very good news!, for DCIS.

Approximately 50 % to 75 % of DCIS express estrogen receptors (ER) and/or progesterone receptors (PR). Systemic treatment, such as hormone therapy, may reduce the chances of developing an invasive breast cancer in the same or the contralateral breast.

Tamoxifen is approved in the U.S.A. to prevent invasive breast cancer recurrence in women with DCIS. For women with ER-positive DCIS who have not undergone a bilateral mastectomy, tamoxifen may be recommended. Tamoxifen reduces the risk of recurrent DCIS in patients treated with breast conservation surgery (BCS) with or without radiotherapy (Staley, 2012).

Are there not any risky side effects in taking a drug, such as Tamoxifen, long term?

Using Tamoxifen long term has an increased risk of post-menopausal bleeding, but cancer of the endometrium is very rare, and easily treated.

The 2013 National Comprehensive Cancer Network (NCCN) Task Force guidelines for risk-reduction management of patients with DCIS include consideration of tamoxifen use for five years (NCCN, 2013).

There are currently no data on the use of aromatase inhibitors in patients with DCIS.

8.7.5 Recurrence Rate for DCIS Following Excision

The Eastern Cooperative Oncology Group (ECOG) 5194 (E5194) is a key observational study that investigated the outcome for DCIS in women when treated by excision alone (Hughes et al., 2009).

Patients studied in ECOG had low- to medium- grade DCIS of < 2.5 cm diameter, and high-grade DCIS of < 1.0 cm in diameter and excision margins of at least 3 mm, with a negative post-excision mammogram. The median follow-up was 6.7 years. The findings of ECOG 5194 were:

Now these figures below for local recurrence rate of breast cancer are VERY encouraging. That is what we like to see.

Local recurrence rate of DCIS at five-years for patients with low or intermediate-grade DCIS was 6.1%.
Local recurrence rate of DCIS at five-years for patients with high-grade DCIS was 15.3%.
The 10-year local recurrence rate for low or intermediate-grade DCIS was 14.6%, with a median follow-up of 8.8 years
Women treated with total mastectomy, are reported to have a 1 % risk of recurrent DCIS within the same breast.

Do not walk behind me, I may not lead.

Do not walk in front of me, I may not follow.

Do not walk beside me either… just go away!

The Van Nuys Prognostic Index (VNPI) is a scoring system used to predict the likelihood of local recurrence following wide excision alone in patients with DCIS. The scoring system (out of 12) analyzes four prognostic factors: patient age, lesion size, excision margin and histologic classification/grade of DCIS (see Section 4).

Figure 8.1 Table: The Van Nuys Prognostic Index

Fig 8-1 breast cancer treatment

I don’t like this table. Why waste energy on it. Just get DCIS treatment, and if it recurs, get treatment again. Simple.

References

Goldhirsch, A., Gelber, R.D., Piccart-Gebhart, M.J., et al. Herceptin Adjuvant (HERA) Trial Study Team. (2013). 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021. (Retrieved November 26^th 2014): https://www.ncbi.nlm.nih.gov/pubmed/23871490

Moja, L., Tagliabue, L., Balduzzi, S., Parmelli, E., Pistotti, V., Guarneri, V., D’Amico, R. (2012). Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 4, CD006243. (Retrieved November 26^th 2014): https://www.ncbi.nlm.nih.gov/pubmed/22513938

More references for this section are on this page

Patient Information

National Cancer Institute. Breast Cancer. (Retrieved December 12 ^th 2014): http://www.cancer.gov/cancertopics/types/breast

FDA (U.S. Food and Drug Administration. (Retrieved January 25 ^th 2015):http://www.fda.gov/

More patient information for this section is on this page

This page is section 8.B in breast cancer treatment. Back to 8A Treatment for Breast Cancer Forward to 8C Treatment for Stage of Breast Cancer