Local perspective: Write ups on breast cancer

naga picture

Singapore nurse on how she allays patients’ fears of breast cancer

Source:            Wednesday, Nov 06, 2013
Mind Your Body, The Straits Times

By Joan Chew

At 15, Ms Nagalingam Saraswathi had her heart set on becoming a nurse. As a member of the St John Ambulance uniformed group in school, she helped nurses at Kwong Wai Shiu Hospital with tasks as small as cutting patients’ nails or feeding them.

In particular, she was “impressed by a staff nurse who looked very smart in her neatly ironed white uniform and cap” and her gentle approach towards elderly patients.

She herself has donned such uniforms for 41 years since graduating from the now-defunct School of Nursing in 1974.

In 1992, she was selected by SGH to train in breast care nursing at The Royal Marsden in London and Royal South Hants Hospital in Southampton.

Ms Saraswathi may be the first formally trained breast care nurse among the 10 to 12 in Singapore.

Over the years, the 60-year-old has introduced initiatives to help patients, such as group exercise classes to promote movement of the arms post-surgery and the practice of teaching patients to drain their wound, so they can be discharged the day after surgery.

The Senior nurse clinician at Singapore General Hospital (SGH) also works with agencies to organise health screenings for the community.

She is widowed and has a 37-year-old son, who is single and an entrepreneur, and a 35-year-old daughter, who is married.

I specialise in caring for patients who are diagnosed with or suspected to have breast cancer because…

It can be devastating for people who are well and active in life to be told that they have breast cancer.

They have many concerns about the diagnosis and treatment, so I provide the assessment and counselling for physical, psychological, emotional, social, spiritual and sexual concerns, as well as answer any questions on treatment.

Breast care nursing is fascinating because…

The nurses ultimately become friends with the patients, with the first meeting determining the extent of their relationship.

Every patient reacts differently when diagnosed with breast cancer. For the nurses, it takes a lot of patience and compassion to relate to patients and work with them on coping strategies.

Almost all patients have the contact numbers of their breast care nurses whom they can call for assistance and support at all times.

One little known fact about breast cancer patients is that…

Most patients can go home and return to their daily activities the day after surgery. They are not as physically weak as most people think they would be.

If I were to give an analogy for what I do, I would be…

A mother who loves her children. When my children are in trouble, I will counsel, advise and help them move on. I continue to love and care for them although my efforts may go unnoticed. I am very happy when they do well and feel good.

A typical day for me…

Starts at 5am. I visit patients in the short-stay ward – the Ambulatory Surgery Centre – at Singapore General Hospital (SGH) before going to the office at 7am. These are patients who will be discharged the day after surgery.

I see between eight and 10 newly diagnosed patients each week I run the breast clinic on Tuesdays and Fridays. On other days, I have about the same number of patients who come to me for follow-up. I help them with tasks such as removing seroma (accumulation of fluid that leaks from damaged blood and lymphatic vessels), cleaning wounds or fitting a prosthesis onto their chests.

I allocate one Saturday each month for research as I am preoccupied during weekdays with patient counselling, ward visits and training of nurses from schools and around the region.

I usually knock off work after 6pm. My son will then pick me up from work for dinner. I reach home at about 8pm and will watch television or read a book before going to bed at 10pm.

I have come across all types of cases…

Through working with patients as well as their families. About 40 years ago, I attended to a patient who had a wound following a mastectomy.

I helped to dress the wound every day at the SGH clinic and went to her house to do the same on weekends. She was the first patient with a very bad wound whom I attended to.

Both she and her family were very appreciative and came to the airport when I left for my studies in Britain in 1992. I had known them for only two months. I was touched and at a loss for words.

A few years ago, a patient in her 20s underwent surgery and even got married while undergoing chemotherapy.

I love patients who…

Have a positive attitude and appreciate my efforts to help them.

People who get my goat are…

Those who give up on themselves.

Things that put a smile on my face are…

Meeting patients who tell me they are doing fine and seeing they are happy.

It breaks my heart when…

I learn that my patients have a cancer recurrence.

Another thing which saddens me is that women are still coming in with large fungus-like growths even though there is widespread information on breast cancer screening.

This might be due to cultural beliefs or the fact that too many women, such as housewives and the elderly, are ignorant about the importance of breast cancer diagnosis and early treatment.

I would not trade places for the world because…

I have never thought of taking on another job.

I believe that everything happens for a reason and, for me, my passion is in caring for breast cancer patients.

My best tip is…

To be conscious of the changes in one’s breasts. Women should do a monthly breast self-examination and go for a mammogram when they reach 40 years old.

Do not delay these checks as they could save your life.

joanchew@sph.com.sg

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Straits Times 14th March 2013 Mind Your Body article

IORT write up small

At the National Cancer Centre Singapore (NCCS), some women with early-stage breast cancer can have breast conserving surgery and radiotherapy in the same operation.

Radiation therapy is required after breast conserving surgery to lower the risk of cancer occurring again in the same breast. But it is usually administered after the operation, over four to six weeks.

Dr Ong Kong Wee, senior consultant at the department of surgical oncology at NCCS, said radiotherapy given during surgery, or intra-operative radiotherapy (IORT), is a new type of treatment.

He, together with consultant radiation oncologist Wong Fuh Yong, carried out the first IORT procedure in June last year at the centre. The radiotherapy is delivered to the tumour bed for 30 to 50 minutes immediately after the tumour is removed.

Studies have shown that this single session of radiotherapy offers the same survival outcome and fewer side effects as conventional radiotherapy of four to six weeks.

For stage 1 breast cancer, the five-year survival rate is about 90 per cent. For stage 2 breast cancer, it is about 80 per cent.

But, as Dr Ong points out, there is no question that survival rate would be the same. The worry is whether the recurrence rate would increase.

Results from the latest trial, still ongoing and headed by University College London in Brita in, show that there is no difference in the recurrence rate, which is about 1.5 to 2 per cent within the first five years.

IORT costs about $7,000 to $8,000 compared with $5,000 to $6,000 for conventional radiotherapy. It is currently not subsidized.

Dr Ong said the IORT opt ion could convince more women not to choose mastectomy, which some do now because they do not want to deal with weeks of radiation treatment.

About 10 to 15 per cent of all cases of breast cancer, particularly those at an early stage, are suitable for IORT, he said.

The size of the tumour must be smaller than 3cm in diameter, and the cancer must not have spread to the lymph nodes. Patients must also be more than 50 years old. Other factors include how aggressive the tumour is and the patient’s responsiveness to hormone treatment.

Of the 15 cases of breast conserving surgery with IORT done so far at the NCCS, only one case required mastectomy to remove the whole breast subsequently.

At least half of the operations were also done using intra-operative ultrasound scanning.

Dr Ho Gay Hui, senior consultant at the department of surgical oncology at NCCS, said the partial radiation delivered by IORT spares a patient’s normal tissue.

This tissue may include the skin of the breast, the remaining breast tissue, underlying ribs, the lung and the heart.

The NCCS will be conducting clinical trials in future to see if the use of IORT can be ext ended to a larger group of breast cancer patients.

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Advances in Breast Cancer Management: Pride of a Woman

by Dr Benita Tan

Source: Medical Grapevine Asia

Breast cancer remains the most common cancer among women worldwide. Of all cancers diagnosed among women in Singapore, almost 30% are breast cancers. The incidence of female breast cancers in Singapore has been steadily increasing from 20.2 per 100,000 women in the period 1968 to 1972 to 60.0 per 100,000 person years in 2005 to 2009.1,2 More than 1,400 women are diagnosed with breast cancer and more than 300 die as a result of breast cancer each year.3

The treatment of breast cancer has changed dramatically in the recent decades, from that radical mastectomy advocated by Halsted in the 1890s, who suggested that ‘breast cancer is a local disorder involving the general body through the axillary gland and a primary area and could be cured by more expansive surgery’, to that proposed by Fisher et al., who considered that breast cancer is ‘a systemic disorder of which the prognosis depends on the control of micrometastases distributed throughout the general body in the early stage.4,5 With this paradigm shift, less invasive surgical procedures have been established; multidisciplinary therapies6, including surgery, drug treatment with chemotherapy, hormonal therapy and molecular targeting therapy, and radiotherapy strategies are based on the biological behaviour of the breast cancer with consideration of the patients’ condition, i.e. personalised treatments.

As breast cancer management evolved with the trends around the whole, breast cancer care in SGH has also made many advances over the past decade, from diagnosis, to treatment options, nursing support and rehabilitation. The correct role of each modality of management in this multidisciplinary approach needs to be understood, especially given the drastic changes in the trends in the management of breast cancer.

Diagnostic Tools

With mammographic breast screening, smaller and non-palpable tumours and early cancers are being diagnosed. Together with the advances in technology, non-operative diagnosis of breast cancer may be made using image guided needle biopsies, as minimally invasive techniques.

Figure 1. Minimally invasive breast biopsy techniques. A: Ultrasound guided core needle biopsy of a breast tumour; B: Mammographic/stereotactic guided vacuum-assisted biopsy (VAB) of an area of suspicious microcalcifications; C: Ultrasound guided vacuum-assisted biopsy (VAB) of a breast nodule; D: MRI guided vacuum-assisted biopsy (VAB) of an MRI detected nodule.

Figure 2. Localisation of non-palpable breast lesions for open biopsy. A: Hookwire localisation (HWL); B: Radioisotope occult localisation (ROLL).

Image guided hookwire localisation for open surgery for non-palpable breast lesions are performed when needle biopsy techniques are not suitable due to the location of the lesion or the breast size, or due to the patient’s choice. This has been the gold standard for many years, but this tends to be more uncomfortable for the patient and has complications associated with the wire. Radio-isotope occult localisation (ROLL), a technique using a radiocolloid injection has been used in many breast centres in Europe7,8 is now also available in SGH. This will, in the future, be extended to surgery of non-palpable breast cancer.

Breast Cancer Surgery

Breast cancer is considered in two components: breast and axilla.

Breast

With better understanding of breast cancer biology and advent of multidisciplinary treatment, surgery for breast cancer has moved away from the mutilating Halsted radical mastectomy to more acceptable approaches. With smaller cancers being diagnosed, breast-conserving surgery (wide excision) followed by local radiation therapy has largely replaced mastectomy in the West as the preferred surgical approach for treating early-stage breast cancer; in Singapore, breast conservation is a rising trend. Long term control of disease as well as patients’ likelihood of surviving their cancer is no different from when their entire breast (and along that, their body image and sexuality) is removed. And when mastectomy is indicated or is chosen by the patient, breast reconstruction is suitable for many women and immediate breast reconstruction is preferred in suitable women for better aesthetic outcome; reconstructive options include autologous flaps and/or breast implants.9

 

Figure 3. Surgery for the breast in breast cancer. A: Simple mastectomy for breast cancer; B: Breast conserving surgery (wide excision) for a small cancer in the upper outer quadrant of the breast; C: Skin sparing mastectomy with immediate autologous musculocutaneous flap reconstruction; D: Post nipple reconstruction of C.

Axilla

Axillary lymph node status at the time of diagnosis is the most important prognostic indicator for women with breast cancer. For almost a century, the standard of care included removing a large number of lymph nodes from the axilla of most breast cancer patients (axillary dissection or clearance). This procedure risks of arm morbidity, particularly lymphedema, sensory loss, and shoulder abduction deficits. Since 2007, sentinel lymph node biopsy10 which is the removal and examination of the first node or nodes in the axilla where cancer cells may metastasise to, has become routine in SGH; using this technique, hundreds of thousands of patients have avoided unnecessary axillary dissections. It involves either a blue dye and/or radiocolloid injection before surgery. If that lymph node contains no cancer, then axillary dissection is not performed: if the first lymph node is cancer-free, the other lymph nodes will almost always be free of cancer as well.

Figure 4. Axillary surgery in breast cancer. A: Lymphedema, a possible complication after axillary clearance; B: Sentinel lymph node biopsy using radiocolloid injection and detection; C: Sentinel lymph node biopsy using blue dye injection.

Radiation Therapy: Accelerated Partial Breast Irradiation (APBI)

Radiation treatments for breast cancer, particularly in those women who do not have a mastectomy, have also advanced during the last 20 years. Until recently, whole-breast radiation had been the standard of care. From long term follow up of trials conducted in the setting of BCS, it is noted that the greater majority of recurrences occur only in the region of the original tumour. Furthermore, it appears that the occurrence of tumours in the same breast that is not near the original tumour happens at a similar rate as the development of new cancer in the other breast. This fact suggests that so-called recurrences in distant part of the breast are probably new cancers in themselves and not related to the original cancer and interestingly, this rate is not decreased even when the whole breast has been irradiated. Hence, for at least some patients, the region of the breast that benefit from post-operative radiation is limited to the volume in the immediate region of the original tumour i.e. the ‘index-quadrant’.11

Important implications and hence, attractiveness of this new paradigm of Abbreviated Partial Breast Irradiation (APBI) compared to whole breast irradiation include benefits of the ability to spare much of the surrounding normal tissue from radiation, such as the skin of the breast, the remaining breast tissue, the underlying ribs, lungs and heart will be spared radiation that it would otherwise receive if the entire breast had been irradiated. Furthermore, because a smaller volume of tissue is treated, the duration of treatment is shorter and can be shortened to as little as one week or even one fraction (hence accelerated) depending on what technique is used.

In National Cancer Centre, Singapore, brachytherapy using multicatheter interstitial implants and intra-operative radiotherapy (IORT) using the Intrabeam device are now available and in the near future, suitable SGH patients choosing breast conserving surgery would be eligible for this treatment. It is important to note that APBI is not suitable for every breast cancer patient.

Brachytherapy (‘short distance treatment’) interstitial implants have a long history in the treatment of cancer. In the setting of breast cancer, they have also proven to be highly applicable. In this treatment, hollow soft, plastic tubes are inserted into the breast to surround the region at risk. This process is performed easily and painlessly under sedation. Treatment is then carried out twice a day (once in the morning and once in the afternoon) for five consecutive days over one week. All these treatment is done on an outpatient basis. During each of these treatments, the patient is connected to a brachytherapy machine which will tread the radioactive source in a predetermined fashion into each of these tubes so as to give a homogenous dose to the target. At the conclusion of the 10th fraction on the last day, the tubes are removed. Patients are able to function normally and painlessly during this week. There are no restrictions with showering and other activities.

IORT using the Intrabeam device is also a form of brachytherapy but it differs in many ways from interstitial implants described above. As the name suggests, the treatment is done during the operation to remove the tumour (or sometimes as a second operation solely to deliver the radiation). When used immediately after removal of the tumour in the definitive BCS, an applicator with a spherical end is inserted into the newly excised cavity. The appropriate sized sphere is selected such that the walls of the tumour cavity can be snugly conformed to the spherical applicator. In this fashion, the entire course of radiation which would have spanned up to six weeks, is delivered safely and accurately in that one single fraction while patient is still under anaesthesia for the wide excision surgery.

Medical Therapy

Medical or systemic therapy involves chemotherapy, targeted therapy and hormonal therapy and in early breast cancer, it is prescribed as adjuvant therapy i.e. drug treatments that are given for a period of time after surgery in order to reduce the risk of recurrence or spread of the breast cancer.

Chemotherapy

In general, courses of chemotherapy are now shorter, lasting from 12 to 18 weeks instead of 24 weeks or even longer. Many of the most dreaded side effects of chemotherapy, particularly nausea and the risk of infection have decreased considerably as a result of the changes we have made in the last 20 years.

In addition, the use of neoadjuvant chemotherapy, i.e. chemotherapy before surgery, which used to be indicated only for locally advanced breast cancers, have shown that it did not result in any inferior disease free or overall survival i.e., it does not compromise on safety as many are concerned that delayed surgery while undergoing systemic treatment is dangerous; but increased the rate of breast conservation. It allows one to observe real time biological response and in those who achieve a pathological complete response (no residual cancer found at surgery), disease free and overall survival were better.12

Targeted Therapy

The most significant advance in the adjuvant therapy of early stage breast cancer came in 2005 in the form of a substance called trastuzumab, or Herceptin. Trastuzumab is an antibody that attacks HER-2, a protein that is present in large amounts in about 20 % of breast cancers. Patients treated with this antibody for a year, along with several months of chemotherapy, reduce the risk of their cancer spreading by 50 %. Adding Herceptin into the neoadjuvant chemotherapy increases pathological response rate as well as disease free survival.13

Hormone Therapy

Even the way in which we use hormonal therapy for early stage breast cancer has changed. For many years, the drug tamoxifen was prescribed for women who had hormone-sensitive breast cancers and it is very effective in reducing the risk of recurrence or spread of the cancer. In the last decade, aromatase inhibitors have been found to work better in menopausal women.14

Genomic Medicine

With the advancement in high throughput technology in the era of genomic or molecular medicine, applications and use in many conditions have increased over the last decade. There are currently two molecular signatures being tested in prospective randomised studies for breast cancer: a 70-gene expression profile, under the name MammaPrint (Agendia, Amsterdam, Netherlands) in the Microarray in Node-Negative Disease May Avoid Chemotherapy (MINDACT) trial and a 21-gene recurrence score, as Oncotype DX (Genomic Health, CA, USA) in the Trial Assigning Individualised Options for Treatment (TAILORx).15

Along with other information, the test results can help in making decisions about whether or not to include chemotherapy in the treatment plan in patients with hormone-sensitive cancers that have not affected the lymph nodes. The Oncotype DX has been used in some of our patients to guide treatment.

Other Investigations Tools

Newer modalities for breast examination such as breast tomography has been promising in research studies, but the feasibility in the screening room as a routine still needs to be evaluated. Together with bone scans, CT scans for metastasis is routinely used in staging of advanced cancer, while the liver ultrasound and chest x-ray are considered in early cancer. Although the use of PET or PET/CT scanning is gaining popularity in some centres, it is not indicated in the staging of clinical stage I, II or operable III breast cancer. FDG PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease. FDG PET/CT may also be useful in identifying unsuspected regional nodal disease and/or distant metastasis in LABC when used in addition to standard imaging studies.16

The Future

Paving the way for the future, research is increasingly important. Better understanding of cancer genomics and cell biology gives hope to personalized medicine, to develop more effective and less toxic drugs; advances in immunology could mean developing targets to enhance our bodies’ ability to fight cancer cells and develop breast cancer vaccines. Epidemiological studies will enlighten us on factors that affect cancer incidence and mortality; it can help us modify our risks, aid the direction of our screening and treatment efforts and improve health care development. There will be a better tomorrow.

Dr Benita Tan, Consultant (General Surgery, SGH), Adjunct Assistant Professor (Duke-NUS Graduate Medical School). MBBS (NUS), MMed (Surgery), FRCS (Edinburgh), FAMS (Gen Surgery). Subspecialty in breast and breast cancer surgery.

Acknowledgements to the following for their contributions and clinical photos:

Breast Service (SGH-NCCS)

Dr Jill Wong, Oncologic Imaging

Dr Raymond Ng, Medical Oncology

Dr Tan Bien Keem, Plastic and Reconstructive Surgery

Dr Wong Fuh Yong, Radiation Oncology

Dr Yong Wei Sean, Surgical Oncology

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Molecular Targeted Therapies for Breast Cancer

A Promising Selective Cure

by Dr Lynette Ngo

Source: Medical Grapevine Asia

Targeted therapies have significantly changed the treatment of breast cancer over the past 10 years. For decades, intravenous cytotoxic chemotherapy has been the hallmark of cancer treatment. It acts by inhibiting rapidly dividing cells, including cancer cells and certain normal tissues. Efforts to improve survival in breast cancer have increasingly been focused on novel drug therapies that interfere with specific molecules and pathways involved in tumour growth and progression. Targeted cancer therapies hold the promise of being more selective for cancer cells than normal cells, thus harming fewer normal cells, reducing side effects, and improving quality of life.

A greater understanding of the underlying biology of breast cancer has led to the recognition that breast cancer is not a single entity, but a heterogeneous disease. Three major clinical subtypes of breast cancer are recognised; (i) hormone receptor-positive breast cancer (tumours expressing estrogen receptors and/or progesterone receptors) (ER- and/or PR-positive), (ii) human epidermal growth factor receptor 2-amplified breast cancer (HER-2 positive) and (iii) triple negative breast cancer (tumours lacking ER, PR and HER-2 overexpression).

The targeted drugs currently available or in development for breast cancer will be discussed in 3 sections; (i) hormone receptor antagonists, (ii) HER2-directed therapy, and (iii) other targeted therapies.

Hormone Receptor Antagonists

Hormone receptor-positive breast cancers comprise the most common type of breast cancer, accounting for up to 65% of all breast cancers. The first molecular target in the development of targeted drugs was estrogen receptor (ER), which hormone receptor-positive breast cancers require for growth. When estrogen binds to ER, the resulting hormone-receptor complex activates the expression of genes involved in cell growth and proliferation. Since estrogen deprivation is the goal in the treatment of hormone-sensitive breast cancer, drug therapies were developed to reduce estrogen production, block signalling through the ER, or degrade the receptor.

Tamoxifen is a selective estrogen receptor modulator (SERM) that specifically competes with estrogen for the binding sites in ER in the breast to exert a cytostatic effect. In early stage hormone-receptor positive breast cancer, Tamoxifen prolongs survival and reduces breast cancer recurrence in both premenopausal and postmenopausal women.1 Tamoxifen has also been proven to improve survival in patients with hormone receptor-positive metastatic breast cancer.2-5

Aromatase inhibitors (AIs) decrease circulating levels of estrogen by blocking the action of the enzyme aromatase, which converts androgens into estrogens in the peripheral tissue. Because the ovaries of premenopausal women can produce enough aromatase to override the inhibition, AIs are contraindicated in premenopausal women. Three AIs are currently commercially available — Anastrozole (Arimidex), Exemestane (Aromasin), and Letrozole (Femara). In postmenopausal women with early stage hormone receptor-positive breast cancer, treatment with an AI results in an increased reduction in the risk of recurrence compared to treatment with Tamoxifen.6 Women who are treated with Tamoxifen for two or three years and then switched to treatment using an AI, also have reduced recurrence rates as well as an increased survival.6 In the first-line treatment of postmenopausal patients with hormone receptor-positive metastatic breast cancer, AIs also have superior overall survival when compared to Tamoxifen.7

Fulvestrant is an estrogen receptor (ER) antagonist. It binds to the ER and promotes its destruction, thereby reducing ER levels inside cells. Studies have shown Fulvestrant to be as effective as AIs and as well tolerated for the treatment of hormone receptor-positive metastatic breast cancer.8.9

Not all patients with hormone-receptor positive breast cancer respond to Tamoxifen or AIs. One of the mechanisms of endocrine resistance is aberrant signalling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway. There is growing evidence of close interaction between the mTOR pathway and ER signalling. Everolimus is a targeted drug which inhibits mTOR. In a phase III study (BOLERO-2), patients with hormone receptor-positive metastatic breast cancer who had progressed on AIs and were treated with a combination of Exemestane and Everolimus had higher overall response rates and improved progression-free survival compared to women who were treated with Exemestane alone. The combination of Everolimus plus Tamoxifen is also an option for patients previously treated with an AI.10

New targeted drug therapies are constantly being explored in clinical trials for patients with hormone receptor-positive breast cancer. Entinostat is a small molecule inhibitor of class I histone deacetylases, which are proteins required for the control of gene expression. It exerts an anti-proliferative effect and promotes apoptosis in breast cancer cell lines. Preliminary results of a clinical trial evaluating Entinostat in women with metastatic hormone receptor-positive breast cancers who had progressed on AIs showed that patients receiving combination therapy with Exemestane and Entinostat had improved progression-free survival compared with patients receiving Exemestane alone.11 Results from confirmatory clinical trials are still pending.

HER-2 Directed Therapy

Signalling through the epidermal growth factor receptor (EGFR) family stimulates growth in breast cancer cells. The most important member of the EGFR family in breast cancer is the transmembrane glycoprotein receptor, HER-2. Approximately 20% of breast cancers overexpress HER-2. Amplification of HER-2 is associated with a worse clinical outcome.

Trastuzumab (Herceptin), a monoclonal antibody that interferes with the HER-2 receptor has been exceptionally successful in both the adjuvant and palliative setting. In HER-2 positive metastatic breast cancer, treatment with Trastuzumab prolongs overall survival.12-14 Adjuvant Trastuzumab after chemotherapy reduces relapse risk, improves disease-free survival as well as overall survival.15 Even upon disease progression, continued HER-2 blockade with Trastuzumab is associated with a longer time to progression of disease.16

Unfortunately, over 50% of HER-2 over-expressing breast cancers are primarily resistant to Trastuzumab. Tumours expressing a truncated form of HER-2 may also not respond to Trastuzumab. A second drug that targets HER-2, as well as other members of the EGFR family, is now available for women with advanced HER-2 positive breast cancer. Lapatinib, in combination with chemotherapy, has demonstrated significant improvement in overall survival when patients with HER-2 positive metastatic breast cancer whose disease have progressed after previous treatment with Trastuzumab.17-19 Lapatinib can also be used in combination with AIs for the first-line treatment of postmenopausal women with HER-2 positive, hormone receptor-positive metastatic breast cancer20 or in combination with Trastuzumab, in patients whose disease has progressed on Trastuzumab.21

Pertuzumab is a new class of targeted drugs which inhibit protein-protein interactions, circumventing Trastuzumab resistance. It is a monoclonal antibody which binds to HER-2 at a region distinct from Trastuzumab, blocking its activation. Binding and activation of this specific region results in interaction with other HER-family receptors and sends growth-promoting signals to the tumour cells.22,23 In a phase III study (CLEOPATRA), first-line treatment of patients with metastatic HER-2 positive metastatic breast cancer who received Pertuzumab, in addition to the combination of Trastuzumab and Docetaxel, revealed an increased progression free survival and overall response rate compared with those who did not.24 An adjuvant trial with dual inhibition of the EGFR signalling pathway using Trastuzumab and Pertuzumab is currently underway.

Trastuzumab emtansine (T-DM1) is a combination of Trastuzumab, conjugated to an antimitotic agent, maytansine (DM1).25 In the phase III EMILIA trial, patients with HER-2 positive metastatic breast cancer who have progressed on Trastuzumab had a longer overall survival, improved response rate and decreased risk of disease progression when treated with T-DM1, compared to treatment with Lapatinib and Capecitabine.26 Moreover, patients treated with T-DM1 had reduced toxicities.

Although Pertuzumab and T-DM1 are not currently commercially available in Singapore, market release of these targeted drugs is in the pipeline in the coming years and holds promise for prolonging survival and improving Trastuzumab efficacy for HER-2 positive advanced breast cancer.

Other Targeted Therapies

Angiogenesis is an important mechanism by which tumours promote their own continued growth and metastasis. Because of the central role that angiogenesis plays, drugs inhibiting the angiogenic cascade have been developed.

Bevacizumab is the first monoclonal antibody developed against vascular endothelial growth factor (VEGF). The landmark E2100 study demonstrated increased response rates and significantly prolonged progression free survival in patients with metastatic breast cancer who had Bevacizumab added to chemotherapy.27 However, Bevacizumab was associated with an increased number of serious side effects, including gastrointestinal bleeding, stroke and wound healing complications. Moreover, subsequent studies did not show an improved overall survival advantage.28-31 Hence, Bevacizumab has now been relegated to the role of a drug which should only be used in a carefully selected population of patients.

Women with hereditary breast cancers have germline BRCA-1 and/or BRCA-2 gene mutation, rendering the cancer cells defective in DNA repair. Poly (ADP-ribose) Polymerase-1 (PARP-1) is a DNA-binding protein involved in detection and repair of DNA strand breaks. Inhibiting PARP in BRCA-mutated cancer cells results in the inhibition of the remaining DNA repair mechanism, resulting in tumour cell death. BRCA-1 and BRCA-2 associated breast cancers are thus particularly sensitive to PARP-1 inhibitors. Triple negative breast cancers are tumours lacking in therapeutic targets such as ER or HER-2. This disease is aggressive and if untreated, has a poor prognosis. Up to 20% of patients with triple-negative breast cancer have BRCA mutations, particularly in BRCA-1 mutations. In a study where women with metastatic breast cancer and BRCA-1 or BRCA-2 mutations were treated with the PARP inhibitor, Olaparib, overall response rates were an impressive 41% without significant toxicityv.32,33 When patients with metastatic triple negative breast cancer were treated with a combination of chemotherapy and another PARP inhibitor, Iniparib, in a phase II study, response rates, progression free survival and overall survival were significantly improved.34 Unfortunately, this benefit could be confirmed in a subsequent phase III trial.35

Conclusion

The era of targeted therapies has contributed to the rapid advancement of breast cancer treatment. Targeted drugs have increased cure rates in localised breast cancer and improved survival in metastatic breast cancer. It is the hope that breast cancer treatment will one day be individualised based on the unique set of molecular targets produced by the tumour. The challenge at present is the need to identify more clinically relevant biomarkers that can predict drug sensitivity and clinical benefit so that medical oncologists can better select appropriate patients for specific targeted drugs and balance relative benefit with risk. The promise of true personalised cancer therapy can only become a reality with more systematically designed biomarker-driven clinical trials.

Dr Lynette Ngo is a Medical Oncologist at the Raffles Cancer Centre. Her areas of interest are in breast and gynaecologic cancers, psychosocial oncology and palliative medicine, in addition to general medical oncology. In pursuing her sub-specialty interest in gynaecologic cancers, Dr Ngo was awarded the Health Manpower Development Programme Award to spend a year at the Gillette Center for Gynecologic Oncology at Massachusetts General Hospital (MGH), USA. In collaboration with the MGH gynaecologic oncology team, she designed and conducted several investigator-initiated clinical trials, testing novel drugs and treatment strategies in subsets of gynaecologic cancers with molecularly defined pathways. She has contributed to numerous publications in peer reviewed journals and written book chapters.

 

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Metastatic Breast Cancer

Is there a role for surgery?

by Dr Felicia Tan

Source: Medical Grapevine Asia

Conventional wisdom and dictum states that “there is no role for surgery in stage 4 breast cancer”. Metastatic breast cancer is considered to be incurable, and the goals of treatment are the prolongation of life and the palliation of symptoms. This same belief has fostered treatment regimens based on the notion that palliative treatment is the optimal choice, with more aggressive surgery likely to result in useless patient distress.

Within this context, it is not surprising that local therapy is not routinely recommended for patients presenting with a stage 4 disease and an intact primary. Surgery is reserved for patients who develop complications such as bleeding, ulceration or infection at the primary tumour site. Surgery for metastatic lesions has also been frowned upon by many oncologists. With improved imaging technology, we are now seeing many women who are diagnosed with stage 4 disease with considerably low tumour burden than were seen in the past. This has led to a stage shift, in which women who would have previously been classified as stage 2 or 3 and treated aggressively with multi-modality therapy are now being classified as stage 4 and treated with palliative therapy.

On the same note, with improved surgical techniques and newer targeted treatments, aggressive multi-modality treatment approaches have occasionally resulted in long-term survival of 15 years or more. This was previously unheard of in metastatic breast cancer.

This article aims to re-address this topic and challenge the validity of the dictum in our current day and age.

Local Breast Surgery

The suggestion that surgery in some patients with metastatic disease may improve survival is not as outlandish as it may initially seem. In a retrospective study of 300 women with metastatic disease at the time of diagnosis published in the Journal of Clinical Oncology, Rapiti et al observed that women having surgery of the primary tumour had a 50% reduction in breast cancer mortality compared with women who did not undergo surgery.1 These results are echoed in another study of 16,023 women presenting with stage 4 disease by Khan et al.2 In this study, surgery of the primary tumour was associated with a 39% reduction in risk of death, with a three-year survival of 35% for patients excised to negative margins, 26% for those with positive margins and 17.3% for those not having surgery (P<0.0001).

The possibility of modified radical mastectomy in stage 4 disease raises concern about unduly aggressive surgical therapy, but one should consider that hospitalisations for such surgery is only two days and the operative morbidity and mortality are extremely rare. These morbidity and mortality statistics compare favourably with the toxicity profiles of many systemic agents used in the metastatic setting.

While it would be naïve to believe that surgery will benefit all women with metastatic disease, clinicians should also recognise the subset of stage 4 patients who would benefit from surgery in combination with multi-modality treatments. Patients who would likely to benefit from surgery would be those with limited metastatic disease (termed oligometastatic disease) and with tumours sensitive to systemic therapy.

Surgery for Breast Cancer Metastasis

With new treatment modalities, there has been significant improvement in median survival times for patients with metastatic breast cancer. Five-year survival rates have improved from 10% 25 years ago, to about 40% today. With these longer median survival times, the treatment paradigm for metastatic breast cancer is evolving. Cancer centres around the world are taking a more aggressive approach for patients with metastatic disease limited to a solitary site. When these patients can be rendered clinically disease-free by local surgical treatment, there is a potential of achieving complete remission from chemotherapy and we are seeing patients disease-free for prolonged periods of time (more than 15 years).

The role of curative surgery in treatment of selected patients with metastatic breast cancer has been reviewed in a meta-analysis published in the journal The Oncologist.3 They concluded that aggressive local therapy (be it surgical, radiofrequency ablation or radiotherapy) is largely beneficial in patients with low tumour burden in metastatic sites, namely the lung, liver, brain and sternum. Across the four sites, better patient outcome after surgery was associated with good performance status, long disease-free interval after treatment of the primary tumour, complete resection of the tumour and restriction of metastasis to single tumours or multiple tumours at a single site.

The last criterion argues for early detection of the metastatic lesion before more advanced disease progression occurs. However, current recommendations for follow-up of breast cancer do not include screening for metastasis unless the patient is symptomatic. This recommendation is based on a large multi-centre trial in Italy performed in a time where detection of metastasis would be treated with palliation, and not aggressive multi-modality therapies. Treatment recommendations will continue to evolve as we see more data supporting an improved prolonged survival for subsets of patient with oligometastatic disease treated with current multi-modality approaches including aggressive surgical treatment.

Summary

The oncology community has come to realise that the approach to treatment of breast cancer is defined by its molecular characteristics. It is about time to realise that palliation may not be an appropriate goal for all women with metastatic breast cancer. Surgery should be considered as part of the armamentarium of multimodality treatment in the metastatic setting to decrease tumour burden and achieve prolonged survival without significant morbidity for some of our patients.

Dr Felicia Tan is a General Surgeon at the Raffles Surgery Centre. Dr Tan’s clinical interest lies in breast oncology and the use of surgical techniques to achieve the best oncologic and cosmetic outcomes for her patients. This includes breast conservation surgery for cancers as well as nipple- and skin-sparing mastectomies with immediate breast reconstruction. She is also adept at the whole range of breast surgical procedures including vacuum assisted biopsies for breast lesions and the radioisotope occult lesion localisation (ROLL) procedure. She continues to perform the full range of general surgical operations. Dr Tan is actively involved in promoting breast cancer awareness both locally and internationally. She is a committee member on breast cancer support groups, and is the scientific medical advisory for the World Conference on Breast Cancer Foundation (WCBCF). She is also a member of Bali’s International Women’s’ Association.