Medical Advancements in Breast Cancer Treatment

8/12/2019 Medical Advancements in Breast Cancer Treatment

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Medical Advancements in

Breast Cancer TreatmentBy Tyler ClaveauBMS 495 02

4/17/2013


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Breast cancer is a heterogeneous disease that will inevitably affect someone we know in

our lives, be it family members, friends, colleagues, or even ourselves. It has been known about

for thousands of years and while new and approved advancements have been made in the

treatment of breast cancer, we still dont have a sure-cure. Weve tried and adapted a

magnitude of treatment regimens that involve a whole spectrum of physicians including:

radiologists, oncologists and surgeons all to help alleviate the illness. Each member of the team

is crucial to the health and well-being of the patients, and also to the integrity of the treatment

regimen. With the help of researchers and geneticists, genetic microarrays have lead to a wide

variety of improvements in the way breast cancer is treated based on specific breast cancer

subtypes. There isnt one set way to go about treating the disease but common methods

include: surgery, irradiation, hormone therapy and chemotherapy depending on the type of

cancer.

Historical Perspective

History shows that breast cancer has been around since the time of the Egyptians, about

3000 to 2500 BC. Eight cases of breast cancer were identified on papyrus, but unfortunately

they had no treatment for the disease. Roughly a thousand years later in India the first reported

cases of treatment with surgical excision were observed and widely adapted. This practice of

treatment wasnt changed much until the end of sixteenth centurywhen Jacques Guillemeau, a

French physician, recommended the removal of the pectoral muscle along with the breast.

Then shortly after, Marcus Aurelius Severinus suggested the removal of the axillary nodes along

with the breast. These combined efforts were the first treatments aimed at what we now know

as malignancy and metastatic cancer. These ideas were expanded upon through the next

thousand years until 1757 when Henry LeDran recorded that breast cancer in its earliest stages

was local and then started to spread to the lymph nodes where it entered into circulation.1


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Surgical Procedures

Surgical removal as a treatment has changed and adapted in many ways to meet the

patients needs. Up until the later 1900s the main surgical procedure performed was the

mastectomy, more specifically, the Halsted mastectomy. The operation involved extensive

removal of the skin and breast tissue, pectoralis major and minor, and axillary lymph nodes.1

This remained the treatment of choice until 1969 when a randomized study was conducted to

compare the radical mastectomy to a breast conserving therapy (lumpectomy) in women with

early stage breast cancer. Women who were treated with the lumpectomy procedure

underwent tumor resection, with removal of sufficient normal breast tissue to ensure both

tumor-free results and satisfactory cosmetic results. The study showed that long-term survival

of women with early breast cancer who were

treated with the breast-conserving procedure

was nearly identical to the rate of women who

underwent the mastectomy, as shown in

figure one.2Also, shown in figure one is the

calculated expected survival for aged-matched

cohorts of Italian women. This was great news

in terms of breast cancer treatment because

the quality of life is much higher with the

breast-conserving therapy.2The radical

mastectomy usually resulted in a gross

deformity and frequent problems with sensory abnormalities in the chest and arms.1

In terms of

psychological health advancements, the lumpectomy was a major improvement, but it could

still be made more efficient. Researchers turned their attention to using high energy particles to

kill the tumor cells.

Addition of Radiation Therapy

By the beginning of the twentieth century, radiotherapy had been shown to be effective

in treating breast cancer. Radiation therapy was not widely used unfortunately due to the lack

of radium the hospitals and researchers could obtain, along with the ability to handle radium

Figure 1. Kaplan

Meier Estimates of Survival after Radical Mastectomy orBreast-Conserving Therapy


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without overexposing themselves. It wasnt until the late 1900s that it became a more widely

used practice, and even then it was rarely used as standalone treatment. Breast irradiation is

typically used in combination with the surgical procedure of lumpectomy. After the surgery is

performed irradiation can begin when the wound healing permits. Typically, the standard

treatment is to deliver radiation in the form of gamma, x-ray, or charged particles externally to

the affected breast, known as External Beam Radiation Therapy.3The goal being to effectively

damage enough of the cancer cells DNA to kill them, while not harming the DNA of the normal

tissue.In particular, a studyconducted in 1985 by Bernard Fisher looked at the treatment results

of using radiation therapy.

Fisher used a radiation dose on patients of 50 Gray (Gy) at a rate of 10 Gy per week.

Gray is simply the SI unit used to measure the amount of radiation energy absorbed by 1

kilogram of human tissue. Typically, the dosage is determined based on the type of cancer, the

diameter of the tumor, and how far the radiation must travel into the tissue.3Though, the

patients medical history and past treatments of radiation are also figured in where applicable.3

In this study they compared women who underwent lumpectomy alone to women who

underwent lumpectomy and radiation therapy for the treatment of intraductal breast cancer.

The results of using the radiation therapy were quite extraordinary. The women who were

treated with radiation had significantly better event-free survival during five year follow-up

than did the women treated with lumpectomy alone. The benefit of radiation therapy came

with its ability to decrease the incidence of second ipsilateral breast tumors (tumors affecting

the same breast).4The decrease of incidence was seen in both noninvasive cancer and invasive

cancer. Another study retrospectively analyzed the data of patients treated during 1999 to

2004 for non-inflammatory locally advanced breast cancers with and without radiation therapy

and found very similar results. There was a significantly lower chance of disease free survival

when patients were not treated with radiotherapy and a significantly lower overall survival.5In

other words, researchers could now utilize radiation therapy with surgical procedures to get

improved treatment results.


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Up until this point, the mastectomy alone was very effective. It ensured the complete

removal of the initial tumor site, along with any surrounding tissue where the tumor may have

spread. Along with removing the axillary nodes it was what physicians thought to be the

greatest tool they had for fighting breast cancer. Unfortunately, because you are removing a

large area of the body, it has a strong psychological detriment to the patients in the form of

extreme deformities. With the innovation of breast conserving therapy paired with radiation

therapy there was a way to fight breast cancer, and cut down on the psychological effects. Still,

many physicians and researchers questioned if the lumpectomy with or without the radiation

therapy was as effective as the mastectomy for treatment. In 1971, the National Surgical

Adjuvant Breast and Bowel Project ran a randomized clinical trial to resolve the question. A

total of 2,163 women with stage one or two breast cancer were randomly assigned to one of

the three treatments: total mastectomy, lumpectomy, or lumpectomy with radiation. Table 1

shows the data collected for all first reported recurrences.6

The study supported the evidence that lumpectomy with irradiation of the breast

decreased the likelihood of a recurrence in the ipsilateral breast. The cumulative incidence of

recurrence in women who underwent the lumpectomy with the irradiation was 14.3 percent,

while for the women who

didnt undergo irradiation it

was 39.2 percent. The study

also strongly concluded that

there was no difference in

overall survival among the

three treatment groups.

Survival was 47 percent

among the mastectomy

patients, 46 percent for the

lumpectomy alone, and 46

percent for the lumpectomy followed by irradiation of the breast; nearly identical. There was

no decrease found in overall survival of the women who underwent the lumpectomy surgery.6

Table 1. First Reported Recurrence and Other First Events *


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Because of the extensive studies done physicians had a new way to combat breast cancer

depending on the progression of the disease. If the cancer had already spread into surrounding

tissue physicians could still utilize the mastectomy procedure, but now if the cancer was

isolated to the breast tissue physicians could use the lumpectomy with radiation for similar

results of survival without the psychological ramifications.

Genetic Microarrays

Using modern gene expressions from DNA microarrays researchers have identified

several breast cancer subtypes that are correlated to hormone receptors, but this isnt the first

time in history that it was observed. In the late 1800s Thomas Beatson found breast cancer to

be hormonally dependent by observing tumor regression after surgical oophorectomy (surgical

removal of an ovary).1

Because the ovaries are the primary site of estrogen synthesis, when the

ovaries were removed the cancer that was dependent on the estrogen for growth would

regress. More modern DNA microarrays (Figure 2) have helped physicians and researchers

tremendously in improving their treatment procedures. Using a technique much like southern

blotting, the microarray in figure 2 shows some of the genes actively expressed in various types

of breast cancer. If a gene is being under expressed it is colored green, and if it is being over

expressed it is colored red. The main genes identified by this microarray were the estrogen

receptor (ER), the human epidermal growth factor receptor (HER1 and HER2), and cytokeratin

Figure 2. Immunohistochemical Identification of Breast Tumor Intrinsic Subtypes


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(CK5). If any of the genes are overexpressed, along with the progesterone receptor (PR), they

can potentially lead to uncontrolled growth and eventually a tumor. The four main subtypes

termed through gene expression were: Luminal A (ER+ and/or PR+, HER2-), Luminal B (ER+

and/or PR+, HER2+), HER2 positive (ER-, PR-, HER2+), and Basal-Like/Triple Negative (ER-, PR-,

HER2-).7Because each subtype is unique, different treatment regimens must be used for each

(Figure 3). If the subtype is actively expressing the estrogen receptor (Luminal A and B), then a

hormone therapy targeted at inhibiting the binding or synthesis of estrogen can be used. But, if

the breast cancer is not over expressing the estrogen hormone receptor (HER2 Positive and

Triple Negative), then chemotherapy is the main option; in some cases of high risk cancer they

can be used in combination with each other for increased treatment benefits.

7

A study performed in 1993 by Christos Sotiriou took tumor samples from 103 patients

with primary breast cancer in order to help observe the effect the estrogen receptor had in the

role of cancer. An independent DNA microarray was performed on the samples and concluded

that the estrogen receptor status of the tumor was the most important discriminator of

expression subtypes. Other clinical features such as lymph node positivity, menopausal status,

Figure 3.Current individualized adjuvant treatment strategies in early-breast cancer using

conventional immunohistochemistry (ER, PR, HER2) as well as novel prognostic tests


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and tumor size were not strongly reflected in the expression patterns. This study confirmed

that estrogen receptor biology plays a central role in breast carcinogenesis defining the

configuration of the tumor.9

This confirmed to researchers and physicians that they had yet

another effective front to fight cancer on. Without DNA microarrays being used to identify

overexpressed genes in the breast tissue, cancer subtypes would never have been identified.

Thankfully, this technology has been utilized to its full potential and a new form of breast

cancer treatment has burst onto the scene, hormone therapy.

Hormone Therapy

Breast cancer subtypes that are ER+/PR+ and HER2- can be treated with hormone

therapy and depending on the risk, can be used in combination with chemotherapy (Figure 3).

One of the common drugs used in hormone therapy is Tamoxifen, a selective estrogen receptor

modulator (SERM). Tamoxifen is an antiestrogen compound that is able to antagonize the

actions of estrogen on the breast tissue through competitive binding,9

shown in figure 4. Along

with Tamoxifen, gonadotropin-releasing hormone analogs (GnRH) are also used in

premenopausal women. The GnRH is used to decrease gonadotropin release and thereby

inhibit estrogen production.10

Since premenopausal women are still producing estrogen in their

ovaries the GnRH assures less estrogen is being synthesized, while the Tamoxifen makes it

harder for estrogen that is being produced to bind to their receptors.

Aromatase inhibitors, such as Exemestane, are also being used in hormonal therapy

because they block the synthesis of estrogen. Three generations of anti-aromatase agents exist.

The first generation and second generation are rarely used anymore because they are toxic and

difficult to

administer,

respectively. The

third generation is

the main focus of

clinical practice. All

three inhibit the last

Figure 4. Mechanism of action of aromatase inhibitors compared with Tamoxifen.


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step of estrogen synthesis. If the drug is steroidal it mimics androstendion and binds

irreversibly to the binding site of aromatase. The non-steroidal inhibitors bind reversibly to the

hem-group of the aromatase.11

Exemestane is a steroidal inhibitor of the enzyme aromatase,

the enzyme responsible for estrogen production in postmenopausal women (Figure 4).12

Therefore, aromatase inhibitors such as Exemestane are aimed towards women who are

postmenopausal.

A study done from 1986 to 1991 by Lisa Ryden looked at comparing the effect of

Tamoxifen treatment versus no Tamoxifen treatment. 564 patients were selected for the trial

and randomized into one of the two groups. They then received either the mastectomy or

lumpectomy procedure followed irradiation of 50 Gy to the breast. While surgery on the breast

was being performed hormone

receptor analyses and DNA

microarrays were done to determine

estrogen receptor content. Of the 564

patients, 262 of them were found to

overexpress the estrogen receptor.

Those in the control group then

received no Tamoxifen while those in

the other group were treated with

Tamoxifen. Patient data was then

collected for 15 years and the

recurrence-free survival (RFS) was

calculated. Figure 5 shows the RFS for

both the control and Tamoxifen

groups and displays them in two graphs. The top graph shows patients over expressing

estrogen and progesterone receptors, and the bottom graph shows patients not over

expressing either. The data concluded that Tamoxifen was effective in increasing overall

survival chances, but only in individuals who were observed to have positive hormone receptor

Figure 5. KaplanMeier estimate for patients according to treatment arm: (a) of recurrence-free

survival (RFS) of ER+/PR+ and (b) of RFS for ER-/PR- (n= 156).


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tumors.13

Tamoxifen was proven to work as adjuvant therapy for treating breast cancer and

was another step in the right direction.

Exemestane was also looked at in many studies and compared to Tamoxifen to

determine the potential benefits of both drugs. Since Exemestane works in a slightly different

way, but effectively provides the same treatment, similar results were expected. Instead, initial

studies found that using an aromatase inhibitor was

preferable to using Tamoxifen for postmenopausal

women. It was also noted that if patients were

already being treated with Tamoxifen, it was

beneficial for them to switch to an aromatase

inhibitor.14 More recently a study done in 2007 by

Charles Coombes compared these two drugs on

patients who were estrogen/progesterone receptor

positive and found almost identical results (Figure

6).15Patients who started a treatment of Tamoxifen and switched to Exemestane had slightly

better disease free survival that patients who only used Tamoxifen during the treatment. They

attributed this to a carry-over effect, meaning that the effects from the previous Tamoxifen

treatment were still present when delivering the Exemestane treatment.15

While both SERMs and aromatase inhibitors provide similar results in terms of disease

free survival, there is a slight difference in the overall cost and adverse side effects for each

hormone therapy. Tamoxifen turns out to be slightly less expensive when used alone rather

than using Tamoxifen and switching to Exemestane. When switching to Exemestane patients

end up paying roughly $4,400 more. The increase in cost is attributed to the increase in time of

disease free survival and the cost of treating most severe side-effects.16

One of the major

downfalls of Exemestane is the higher increased risk of osteoporosis (estrogen deficiency induces

bone loss by upregulating osteoclastogenesis17); 7.4% of patients end up having to be treated for

osteoporosis when taking Exemestane. The increase in cost is seen because patients who take

aromatase inhibitors must also take Bisphosphonates to help prevent the osteoporosis.18

Each


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hormone therapy provides something slightly different for patients, and leaves the door open

for more research to be done in the area to hopefully improve results. Still, as of now hormone

therapy has increased the time of disease free survival and is a viable option for patients who

have been diagnosed with ER+/PR+ cancer. Although, hormone therapy isnt appropriate for

patients who are HER+, a different form of treatment must be looked at.

Targeting HER2 and Chemotherapy

Breast cancer subtypes that are HER2+ but not hormone receptor positive can be

targeted by a different form of drugs such as Trastuzumab, a monoclonal antibody, that are

aimed at inhibiting the signaling pathway (Figure 3). Its important to note that the human

epidermal growth factor receptor normally plays an important role in cell growth, survival, and

differentiation in a complex manner. It isnt until the HER2 is involved in dimerization with

other HER members that it causes cell proliferation and prevents apoptosis. The overexpression

of HER2 usually results in malignant transformation of cells and is seen in about 25% of all

breast cancers. It has also been associated with more aggressive tumors, a greater chance of

lymph node involvement, and an increased resistance to endocrine therapy (ER+ breast cancer

treatment).19

The drug Trastuzumab, used to treat metastatic breast cancer, has been shown to

induce apoptosis by suppressing the dimerization of the HER families. A study published in 2001

by Dennis Salmon randomly

assigned 469 patients to

receive chemotherapy alone or

chemotherapy plus

Trastuzumab. Chemotherapy

consisted of an anthracycline

plus cyclophosphamide for

patients who had never

received an anthracycline, or

paclitaxel for patients who had


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received adjuvant anthracycline before. Table 2 shows the data obtained after analysis of the

end points.20

The study found that using Trastuzumab in combination with chemotherapy reduced

the relative risk of death by 20 percent. It also increased the median time to disease

progression, increased the median time to treatment failure, and increased the median survival

time of the patients. Unfortunately, 25 percent of the patients who had the Trastuzumab

treatment did experience chills and fever, while 47 percent ended up obtaining an infection.

Also, in 10 percent of the patients adverse cardiac events were seen. Still, Trastuzumab when

combined with chemotherapy can help patients who are suffering from metastatic breast

cancer that over expresses HER2.20

That is, 25 percent of all breast cancers now had a drug that

had synergist effects to increase overall treatment.

Much like breast cancer itself, the treatment is also continuously evolving. From 3000

BC to the 21st

century, researchers and physicians have been working together to expand their

knowledge of this heterogeneous disease. Utilizing our generationstechnological

advancements we have further broken down the general definition of cancer into distinct

subtypes. Each subtype is unique, requiring different approaches to effectively treat the patient

with the greatest possible outcome. Medical advancements have been made in almost every

way including: new surgical procedures to more efficiently remove tumor tissue, radiation to

kill anti-apoptotic cells, targeting specific receptors that are overexpressed, and using variations

of different treatments in combination with each other for synergistic results. As more

advancement in technology is made researchers will continue to learn more about the

causation of this deadly disease, and inevitably even better and more effective treatments will

follow.


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References

1. M. Akram, S. A. Siddiqui, Breast cancer management: Past, present and evolving. IndianJ. Cancer. 49, 277-282 (2012).

2. U. Veronesi et al., Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N. Engl. J. Med. 347,1227-32 (2002).

3. National Cancer Institute. (June 30, 2010). Radiation Therapy for Cancer. In NationalCancer Institute. Retrieved May 4, 2013, from

http://www.cancer.gov/cancertopics/factsheet/Therapy/radiation#r1.

4. B. B. Fisher, Lumpectomy Compared with Lumpectomy and Radiation Therapy for theTreatment of Intraductal Breast Cancer. N. Engl. J. Med. 328, 1581-1586 (1993).

5. J. But-Hadi, C. Bilban-Jakopin, V. Hadi, The Role of Radiation Therapy in LocallyAdvanced Breast Cancer. Breast J. 16, 183-188 (2010).

6. B. Fisher et al., Twenty-Year Follow-up of a Randomized Trial Comparing TotalMastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of

Invasive Breast Cancer. N. Engl. J. Med. 347, 1233-1241 (2002).7. L. L. A. Carey, Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer

Study. JAMA: The Journal of the American Medical Association. 295, 2492-2502 (2006).

8. N. Harbeck, M. Salem, U. Nitz, O. Gluz, C. Liedtke, Personalized treatment of early-stagebreast cancer: Present concepts and future directions. Cancer Treat. Rev. 36, 584-594

(2010).

9. C. Sotiriou et al., Breast Cancer Classification and Prognosis Based on Gene ExpressionProfiles from a Population-Based Study. Proc. Natl. Acad. Sci. U. S. A. 100, 10393-10398

(2003).

10.L. S. Perlow, J. F. Holland, Chemotherapy of breast cancer. Medical Oncology. 1, 169-192(1984).

11.M. Dank, The role of aromasin in the hormonal therapy of breast cancer. PathologyOncology Research: POR. 8, 87-92 (2002).

12.T. K. Choueiri, C. A. Alemany, R. M. Abou-Jawde, G. T. Budd, Role of aromatase inhibitorsin the treatment of breast cancer. Clin. Ther. 26, 1199-1214 (2004).

13.L. Rydn et al., Two years of adjuvant tamoxifen in premenopausal patients with breastcancer: a randomised, controlled trial with long- term follow-up. Eur. J.

Cancer. 41, 256-264 (2005).

14.J. Cuzick, Aromatase inhibitors in early breast-cancer treatment: The story so far. TheBreast. 17, Supplement 3, 2-8 (2008).

15.R. Coombes et al., Survival and safety of exemestane versus tamoxifen after 23 years'tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. The

Lancet. 369, 559-570 (2007)

16.D. Thompson et al., Cost-Effectiveness of Switching to Exemestane after 2 to 3 Years ofTherapy with Tamoxifen in Postmenopausal Women with Early-Stage Breast Cancer.

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17.Cenci S, Weitzmann M N, Roggia C. et al. Estrogen deficiency induces bone loss byenhancing T-cell production of TNF-alpha. J Clin Invest. 2000;106(10):122937.


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18.H. T. Mouridsen, N. J. Robert, The role of aromatase inhibitors as adjuvant therapy forearly breast cancer in postmenopausal women. Eur. J. Cancer. 41, 1678-1689 (2005).

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20.D. D. J. Slamon, Use of Chemotherapy plus a Monoclonal Antibody against HER2 forMetastatic Breast Cancer That Overexpresses HER2. N. Engl. J. Med. 344, 783-792(2001).

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Medical Advancements in Breast Cancer Treatment