Neoadjuvant breast cancer treatment

Candidates for neoadjuvant chemo therapy or combination treatment if they have molecularly high risk disease according to one of the available molecular assays.

The use of preoperative chemotherapy is standard of care for patients with early-stage breast cancer.

No difference in disease free survival or overall survival based on timing of chemotherapy relative to surgery for breast cancer.

Almost all triple negative and HER2 positive tumors are molecularly high risk.

In patients with triple negative breast cancer and HER2 positive breast cancer, rates of pathological complete response to neoadjuvant chemotherapy is reported to be approximately 60 to 80%:suggesting that some patients who receive neoadjuvant systemic therapy might not require breast and Notal surgery.

High risk tumors include those that measure at least 2.5 cm on examination or 2 cm by imaging.

Tumors that are clinically high risk but molecularly low risk are often offered neoadjuvant endocrine therapy.

Neoadjuvant chemotherapy has resulted in DFS and OS rates equivalent to those achieved with adjuvant chemotherapy, while yielding a 10% to 30% increase in eligibility for breast conservation treatment.

Neoadjuvant therapy increasingly popular.

Neoadjuvant therapy has expanded beyond initial role in downstaging of tumors to accomplish surgery in patients with locally advanced breast cancer.

Neoadjuvant therapy allows for early evaluation of response or resistance to therapy, in terms of reduction of the proliferation index or the achievement of complete pathological response.

Neoadjuvant therapy provides for real-time examination of tumor tissue, imaging results, an biomarkers in response to systemic therapy.

While neoadjuvant therapy has equivalent efficacy to adjuvant therapy, and it has some additional benefits that include increasing breast conservation, assessing tumor response, establishing prognosis based on the pathological response, and providing a second opportunity for nonresponding patients.

NAT is now the preferred approach for the majority of patients with early TNBC at least 2 cm in diameter or node positive, where is upfront surgery is generally reserved for smaller, node negative tumors.

Pathological complete response to neoadjuvant therapy is important prognostic factor in locally advanced breast cancer, but such prognostic information is primarily relevant in triple negative breast cancer and HER2 positive subtypes.

The residual cancer burden index and pathological complete response are highly prognostic in patients with TNBC and post neoadjuvant treatment escalation improves long-term outcomes for patients with TNBC with residual following NAT.

Neoadjuvant therapy has proven to be cost‐effective by reducing nondrug costs, avoiding radical surgery, and reducing hospital stays when compared with other treatment approaches.

The neoadjuvant setting is a powerful model for the development of new drugs and the identification of prognostic markers.

When delivering cancer chemotherapy while of breast tumor is still intact allows the opportunity to observe in vivo rresponsiveness of the lesion before surgical resection and 2 also therapy if appropriate responses is not found.

Permits a response-guided approach that results in longer disease free survival, particularly in hormone receptor positive tumors.

Neoadjuvant therapy allows assessment of drug efficacy rapidly.

Patients with hormone receptor negative, high grade, or HER2 positive tumors are more likely to respond to neoadjuvant chemo therapy.

Achieving pathological complete remission because of neoadjuvant therapy has been correlated with long‐term clinical benefit, particularly in HER2‐positive and triple‐negative breast cancer.

The addition of trastuzumab to chemotherapy in neoadjuvant therapy for patients with HER-2 positive disease improves pathological complete remission rates, disease-free survival, event free survival, and overall survival.

Pathologic complete remissions (pCR) correlate with long-term outcomes, and indicate that in patients with the most aggressive tumor subtypes it provides the best prognostic value.

pCR indicates eradication of tumor from the breast and axillary lymph nodes with or without residual carcinoma in situ.

pCR has a strong association with improved event-free survival and overall survival than tumor eradication from breast alone.

pCR Has long-term benefits for patients, with the strongest association observed for more aggressive breast cancer subtypes such as triple negative breast cancer and HER2 positive disease.

With pCR selected patients can avoid surgery.

Tumor infiltrating lymphocytes associated with a higher rate of pathologic complete remission in the neoadjuvant setting.

Patients who attain pCR have a 64% reduction in the risk of death compared with patients who have residual tumor at the time of surgery.

I-SPY Trial three year outcome showed that regardless of subtype and/or treatment regimen achieving a pathologic complete response after neoadjuvant therapy implies approximately 80% reduction in recurrence rate.

Patients with breast cancer who a complete clinical remission following neoadjuvant chemotherapy who do not undergo surgery have no significant difference in five-year overall survival compared to patients with the pathologic CR following surgery.

The highest pCR rates are found in aggressive tumors subtypes such as triple-negative breast cancer with a rate of 33.6%, HER-2 positive/hormone receptor-negative breast cancer treated with trastuzumab at 50.3%, or without trastuzumab 30.2%, and grade 3 hormone receptor positive/HER-2 negative breast cancer 16.2%.

The prognostic value of pathologic complete response is greatest in patients with aggressive subtype tumors, with the risk of death reduced by 84% in T NBC, 92%, in HER-2 positive/hormone receptor negative breast cancer treated with trastuzumab, 71% in those that did not receive trastuzumab, and 71% and high-grade hormone receptor-positive/HER-2 negative breast cancer.

Pathologic complete response associated with improved event free survival and overall survival, and this is especially true in human epidermal growth factor receptor 2-positive (HER-2+)/hormone receptor negative tumors and triple negative tumors.

Among patients with TNBC, the percentage of patients with pathological complete response is significantly higher among patients who receive  pembrolizumab plus neoadjuvant chemo therapy than among those who receive placebo plus neoadjuvant chemo therapy ( Schmidt P).

Neoadjuvant therapy is currently the preferred management for the majority of patients with early TNBC of at least 2 cm in diameter or node positive, whereas upfront surgery is reserved for smaller, node negative tumors.

The pathological complete response rate is highly prognostic in patients with TNBC. 

 Postneoadjuvant treatment escalation improves long-term outcomes for patients with TNBC with residual disease following neoadjuvant therapy.

Cytotoxic chemotherapy remains the mainstay of neoadjuvant therapy for early TNBC.

Anthracyclines and taxanes regimens remains standard for most patients with localized TNBC.

The addition of carboplatinum to anthracycline in taxing base regimens increases the pathological response rate.

The addition of checkpoint inhibitors added to chemotherapy significantly improves pathological complete response rates by greater than 70% and is approved;  pembrolizumab is approved for the treatment of high risk early TNBC.

In neoadjuvant therapy the primary endpoint, pCR, may be achieved in a much shorter period of time than traditional endpoints of disease-free survival or overall survival.

NeoSphere study added pertuzumab for locally advanced, inflammatory, or early stage HER2 positive breast cancer to doctaxel and trastuzumab resulting in 18% improvement in pathologic complete response rate.

NeoAltto randomized trial evaluating neoadjuvant lapatinib and trastuzumab combination therapy in her 2 positive operable breast cancer: pCR was significantly higher in the combination group, particularly in hormonal receptor-negative tumors.

The addition of Durvalumab and Parp inhibitors to standard paclitaxel neoadjuvant chemotherapy increases pathological complete remission rates in stage II or III HER2 negative breast cancer.

ICIs Improve pCR Rates in Early ER+/HER2– Breast Cancer

Evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status.

In the Checkmate 7FL trial the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone.

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