Running head: INTEGRATIVE REVIEW 1

HER2 Positive Breast Cancer

Crystal Owens

Bon Secours College of Nursing

Research 4122

Arlene Holowaychuk, MSN

November 12, 2017

I pledge
INTEGRATIVE REVIEW 2

Abstract

This integrative review was done to appraise literature related to the outcomes of neoadjuvant

versus adjuvant therapy with Trastuzumab (Herceptin) on human epidermal receptor 2 (HER2)

positive breast cancer on overall survival and or pathological complete response (PCR). HER2

positive breast cancer is known to have higher reoccurrence, metastasis rates, shorter disease-free

survival, and overall survival. EBSCO database was used to search for pertinent literature. The

search presented 427 articles relating to the subject. These articles clearly discussed findings

related to outcomes of treatment involving Trastuzumab, although each article discusses other

chemotherapy agents that were also involved with treatment. Due to the different staging and

other chemotherapy agents used in these treatments there are limitations in this review. More

research needs to be done and this is difficult since each case of cancer is different. A lot of

studies pertaining to the topic were reviewed but there is not a clear answer to this PICOT

question since every case and outcome was different.

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Integrative Review

Breast cancers that express high levels of human epidermal growth factor receptor 2

(HER2) are more likely to spread, resist treatment, and reoccur. After this discovery was made

the drug Trastuzumab (Herceptin) was developed. This drug improved survival rates in stage I-

III by more than 30% ("NCI Discovers: Linking HER2 to Breast Cancer and Beyond," n.d.). It

has been noted that resistance to Trastuzumab can develop over time. The purpose of this review

is to examine literature that answers the PICOT question; in breast cancer patients with HER2

over expression, what is effect of neoadjuvant therapy with Trastuzumab on survival compared

to adjuvant therapy over five years. The researcher has an interest in this type of cancer because

her mother was diagnosed with stage III HER2 positive breast cancer and wanted to know more

about the odds of survival with her chemotherapy treatment plan. Neoadjuvant therapy is often

used to shrink tumors before surgery takes place to make it easier for removal and improves the

chances of getting clean margins. Adjuvant treatment is chemotherapy that is started after the

surgical removal of the tumor.

Design and search methods

This review is based on five research articles that were obtained through EBSCO

Discovery Services. The terms that were used to find these articles included “HER2 positive

breast cancer”, “neoadjuvant”, “adjuvant”, and “Trastuzumab” and yielded a result of 325

articles. These results were narrowed down to recent articles that had been published in the last

five years and were useful in addressing the PICOT question; in breast cancer patients with

HER2 over expression what is effect of neoadjuvant therapy with Trastuzumab on survival

compared to adjuvant therapy over five years. Each article used for this review are quantitative

and related to the PICOT question.

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Findings and results

The overall results from these studies indicate an improved prognosis, especially if they

obtain a pathological complete response (PCR) after neoadjuvant treatment that includes

Trastuzumab. Although response rates vary across breast cancer subtypes getting pathological

complete response has the strongest association for survival in those with HER2 positive breast

cancer. These articles examined several other cancer drugs that were used in combination with

Trastuzumab since most cancers are treated with drug combinations to have a more aggressive

impact on the cancers growth. It’s important to note that although other drugs are used,

Trastuzumab was the first drug designed specific to target the HER2 receptors directly. These

studies were hard to interpret due to the complexity of the information provided.

Neoadjuvant therapy

One article was based on a retrospective study that analyzed stage I-III breast cancer

patients who received neoadjuvant therapy from 2010 to 2015. This study examined other

subtypes of cancer, as well as HER2 noting differences in responses. It was noted that the NOAH

trial resulted in in a 36% reduction in death at five years when Trastuzumab was part of the

neoadjuvant treatment and increased the chance of getting pathological complete response by

20% in those who tumors were positive for overexpression of HER2. (McFarlund, Naikan,

Rozenbit, Mandeli, Bleweiss, and Tiersten, 2015) Statistical analysis was used to assess

pathological complete response rates after neoadjuvant therapy and considered tumor and patient

characteristics. Out of 113 total participants, 43 were HER2 positive and 41.9% had a

pathological complete response.

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Adjuvant therapy

The article by Gonzalez, (2014), reviewed the impact of adjuvant therapy with

Trastuzumab on patients who achieved a pathologic complete response. These patients were

treated between 2001 and 2012. It is noted in the article that adjuvant therapy of Trastuzumab

did not become the standard of care until 2006. Kaplan Meier was used to estimate the overall

survival of this population. According to this study 91% had five-year overall survival estimate

who did not have adjuvant Trastuzumab after PCR and 93% for those that did.

Drug Resistance

Resistance to Trastuzumab has become a concern in the clinical setting even though this

drug has been successful. One study set out to study the results of those who has been treated

previously and then retreated when the disease reoccurred and metastasized. The researchers

conducted a retrospective review of 513 patients with HER2 positive breast cancer with only 353

examined in this primary analysis to include only those staged I-III (Murthy, et al., 2014). The

subjects studied had received Trastuzumab as a first line treatment in either the adjuvant or

neoadjuvant setting. Logistic regression determined the association between prior Trastuzumab

treatment and response to the second treatment after metastasis. Estimation of overall survival

was determined with Kaplan Meier. The researcher concluded that overall survival was 36

months for those who did not have prior Trastuzumab and 28 months for those who did.

(Murthy, et al 2014) Although Trastuzumab is a successful drug prior exposure should be taken

into consideration if treated again after reoccurrence.

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Discussion/Implications

The results of the reviewed literature demonstrate a better pathological complete response

for those who receive neoadjuvant Trastuzumab than those who received adjuvant therapy only.

It has been noted that pathological complete response tends to have a better overall five-year

survival rates. Most of the literature reviewed supports the PICOT question asked by the

researcher. Not every study that was reviewed showed a great difference in survival, however,

outcomes it did demonstrate a better chance of complete pathological response which can

contribute to better chances of survival.

Limitations/Conclusions

While there is a good deal of literature on the subject available, there are limitations to

this study. The articles that were reviewed looked at studies that incorporated different stages of

cancer and some included subtypes other than HER2 positive tumors which made interpretation

difficult to the lay person. This was the researchers first integrative review and the nature of the

subject was very complex and difficult to understand due to limited medical education.

Treatments that were examined incorporated several other chemotherapy agents such as Taxanes,

Anthracycline, and Carboplatin containing chemotherapy agents that may need to be taken into

consideration when examining results. With so many options and combinations of drugs used to

treat cancer it is not a one size fits all treatment even for HER2 positive cases. There were also

varying numbers of cycles of chemotherapy given to different subjects.

In conclusion, neoadjuvant Trastuzumab in HER2 positive breast cancer staged I-III has a

better chance of pathological complete response than just used in adjuvant setting. Pathological

complete response is better associated with a five-year overall survival. Resistance to

Trastuzumab is noted to develop usually within the first year of treatment. Changing
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chemotherapy agents when the disease metastases may help to partially overcome that. More

research for new drugs to combat this type of aggressive cancer is needed. It appears that those

who received neoadjuvant treatment with Trastuzumab have better odds of survival at five years

when they have a complete pathological response as compared to those who had only adjuvant

treatment.
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References

Gonzalez-Angulo, A. M., Parinyanitikul, N., Lei, X., Mittendorf, E. A., Zhang, H., Valero, V., &

... Chavez-MacGregor, M. (2015). Effect of adjuvant trastuzumab among patients

treated with anti-HER2-based neoadjuvant therapy. British Journal Of Cancer, 112(4),

630-635. doi:10.1038/bjc.2014.647

McFarland, D. C., Naikan, J., Rozenblit, M., Mandeli, J., Bleiweiss, I., & Tiersten, A. (2016).

Changes in Pathological Complete Response Rates after Neoadjuvant Chemotherapy for

Breast Carcinoma over Five Years. Journal of Oncology, 20164324863. Doi:

10.1155/2016/4324863

Krishnan, Y., Al Awadi, S., Sreedharan. P.S., Sujith Nair, S., & Thuruthel, S. (2016). Analysis of

neoadjuvant therapies in breast cancer with respect to pathological complete response,

disease free survival and overall survival: 15 years follow up data from Kuwait. Asia-

Pacific Journal of clinical oncology, 12(1), e30-e37. Doi:101111ajco.12118

Murthy, R. K., Varma, A., Mishra, P., Hess, K. R., Young, E., Murray, J. L., Koenig, K. H.,

Moulder, S. L., Melhem-Bertrandt, A., Giordano, S. H., Booser, D., Valero, V.,

Hortobagyi, G. N. and Esteva, F. J. (2014), Effect of adjuvant/neoadjuvant trastuzumab

on clinical outcomes in patients with HER2-positive metastatic breast cancer. Cancer,

120: 1932–1938. doi:10.1002/cncr.28689

NCI Discovers: Linking HER2 to Breast Cancer and Beyond. (n.d.). Retrieved from

www.cancer.gov/research/progress/discovery/HER2

Zhang, W., Tian, H., & Yang, S. (2017). The Efficacy of Neoadjuvant Chemotherapy for HER-

2-Positive Locally Advanced Breast Cancer and Survival Analysis. Analytical Cellular

Pathology: Cellular Oncology, 1-5. doi:10.1155/2017/1350618

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First Author A M Gonzalez-Angulo 2015

(Year)/Qualifications
Background/Problem Researchers want to analyze the impact of pathologic
Statement complete response after trastuzumab based neoadjuvant
treatment.

Conceptual/theoretical Not discussed

Framework

Design/ Retrospective review of the Breast Medical Oncology

Method/Philosophical database.
Underpinnings

Sample/ A total of 589 women with HER2 positive breast cancer

Setting/Ethical diagnosed between 2001 and 2012. Two authors received
Considerations funding from Genetech and GSK. All other authors have
declared no conflicts of interest.
Major Variables Patients with various subsets of breast cancer were studied
Studied (and their and outcomes were evaluated based on tumor and patient
definition), if characteristics and whether or not they received adjuvant or
appropriate neoadjuvant therapy.

Measurement Kaplan Meier was used to estimate the 5-year overall

Tool/Data Collection survival. Cox proportional hazard model was used to
Method determine clinical characteristics with survival outcomes.
Chi square test was used to tabulate characteristics
between adjuvant vs no adjuvant groups.

Data Analysis
Findings/Discussion 5 year OS were 91% for those who did receive adjuvant
therapy and 93% for patients who did.

Appraisal/Worth to These results only showed a slight increase in benefit to

practice receiving adjuvant therapy.
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First Author Wei Zhang MD 2017 Department of breast surgery

(Year)/Qualifications Guanghou University of Chinese Medicine
Background/Problem Human epidermal growth factor receptor 2 subtype of
Statement breast cancer has a high metastasis and mortality rate
and short overall survival.
Conceptual/theoretical To analyze the efficacy and influencing factors of
Framework neoadjuvant chemotherapy on patients with HER2
positive breast cancer.

Design/ Retrospective study.

Method/Philosophical HER 2 locally advanced breast cancer patients underwent
Underpinnings treatment from November 2010 to July 2016 and
influencing factors were examined to evaluate survival
rates.
Sample/ 119 women with HER2 positive breast cancer
Setting/Ethical The authors declare no conflict of interest.
Considerations

Major Variables Retrospective study of patient with invasive cancer

Studied (and their diagnosed with needle biopsy before chemotherapy with
definition), if clinical staging of II-III, HER2 positive subtype by
appropriate immunohistochemically testing.

Measurement Survival was analyzed using the Kaplan-Meier method that

Tool/Data Collection used log rank tests to determine survival curves.
Method Clinical data regarding treatment and follow up was
reviewed.
Response evaluation criteria in Solid Tumors was used to
evaluate disappearance of all known lesions.

Data Analysis Almost all patients with PCR survived the study whereas
59% of those who did not achieve PCR had disease free
survival of about 3 years.

Findings/Discussion Neoadjuvant chemotherapy can increase Pathological

complete response (PCR) and increase long term survival
rates.

Appraisal/Worth to Adding additional Trastzumab based cycles to treatment

practice plan should be considered.
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First Author Krishnan, 2013 MD specializing in medical oncology

(Year)/Qualifications
Background/Problem Neoadjuvant therapy in the last decade has increased
Statement because of it allows downstaging of the tumor and
helps increase rates of breast conserving surgery.

Conceptual/theoretical These researchers wanted to analyze pathological

Framework complete response (PCR) with respect to various
neoadjuvant regimens and its effect on survival.
Design/ Retrospective quantitative analysis
Method/Philosophical
Underpinnings

Sample/ 377 patients with stage II or stage III breast cancer treated
Setting/Ethical with neoadjuvant therapy.
Considerations

Major Variables Neoadjuvant therapy was analyzed with respect to

Studied (and their pathological complete response, disease free survival, and
definition), if overall survival.
appropriate

Measurement Kaplan Meier was used to estimate the progression free

Tool/Data Collection survival and overall survival.
Method

Data Analysis There is an increasing PCR with a higher number of cycle’s

given before surgery. 34% PCR in patients that received
trastuzumab neoadjuvant as compared to 11.8% in the
group that did not get neoadjuvant trastuzumab.

Findings/Discussion Patients who received trastuzumab had better results with

respect to 5 year overall survival.

Appraisal/Worth to This study recommends HER2 positive patients receive

practice neoadjuvant trastuzumab followed by maintenance
showing overall survival benefits persisting even at 8 years.
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First Author Rashmi Murthy MD 2014 Medical oncologist

(Year)/Qualifications
Background/Problem To evaluate outcomes of early stages HER2+ breast
Statement cancer patients who received Trastuzumab adjuvant or
neoadjuvant and were subsequently retreated with
trastuzumab for metastatic disease.

Conceptual/theoretical Researchers wanted to compare outcomes of those who

Framework had no prior exposure to trastuzumab to those who had it
as a first line therapy.
Design/ Non experimental Retrospective study. Sample size of 353
Method/Philosophical patients with HER2+ breast cancer.
Underpinnings

Sample/ 353 patients with metastatic disease. 75 had received

Setting/Ethical adjuvant or neoadjuvant trastuzumab for early breast
Considerations cancer and 278 had not received the drug.

Major Variables The variables relevant to this study looked at patients who
Studied (and their were treated with trastuzumab as a first line treatment in
definition), if the adjuvant/neoadjuvant setting and patients who were not
appropriate treated with trastuzumab initially.

Measurement Patients were found through the Department of Breast

Tool/Data Collection Medical Oncology database that is managed through the
Method University of Texas MD Anderson cancer center. Survival
was calculated using the Kaplan- Meier method.

Data Analysis Median survival was estimated to be 36 months in those

without prior treatment with trastuzumab compared to 28
months in patients who had received trastuzumab in the
adjuvant/neoadjuvant setting.
Findings/Discussion This retrospective study of patients who received
Trastuzumab as a first line therapy for metastatic disease
experienced a better overall response as compared to
those who received the drug in the adjuvant or neoadjuvant
setting.

Appraisal/Worth to
practice
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First Author Daniel McFarland 2016

(Year)/Qualifications
Background/Problem This study was done to determine PCR rates before
Statement and after the implementation of neoadjuvant therapies.

Conceptual/theoretical To review their single institution experience with PCR after

Framework neoadjuvant therapy over a 5-year period.

Design/ Retrospective quantitative

Method/Philosophical
Underpinnings

Sample/ A sample size of 113 patients who received NCAT. They

Setting/Ethical declared no conflict of interest.
Considerations

Major Variables Stage I-III patients treated with neoadjuvant chemotherapy

Studied (and their from March 2010-March 2015
definition), if
appropriate

Measurement Participants were identified through pathology department

Tool/Data Collection database at Ichan School of medicine and was approved
Method through their IRB.

Data Analysis Chi squared tests used to determine associations between

variables. Independent T test used to assess associations
between variables and PCR.

Findings/Discussion 36% reduction in death at 5 years when Trastuzumab was part of

the neoadjuvant treatment and increased the chance of getting
pathological complete response by 20% in those who tumors
were positive for overexpression of HER2

Appraisal/Worth to
practice There are improved PCR rates with the use neoadjuvant
therapy especially for HER2 and TNBC.