Posts Tagged ‘neoadjuvant therapy’

Chemotherapy Benefit in Early Breast Cancer Patients

Larry H Bernstein, MD, FCAP, Curator



Agendia’s MammaPrint® First and Only Genomic Assay to Receive Level 1A Clinical Utility Evidence for Chemotherapy Benefit in Early Breast Cancer Patients


  • Clinical high-risk patients with a low-risk MammaPrint® result, including 48 percent node-positive, had five-year distant metastasis-free survival rate in excess of 94 percent, whether randomized to receive adjuvant chemotherapy or not
  • MammaPrint could change clinical practice by substantially de-escalating the use of adjuvant chemotherapy and sparing many patients an aggressive treatment they will not benefit from
  • Forty-six percent overall reduction in chemotherapy prescription among clinically high-risk patients

April 19, 2016 / B3C newswire / Agendia, Inc., together with the European Organisation for Research and Treatment of Cancer (EORTC) and Breast International Group (BIG), announced results from the initial analysis of the primary objective of the Microarray In Node-negative (and 1 to 3 positive lymph node) Disease may Avoid ChemoTherapy (MINDACT) study at the American Association for Cancer Research Annual Meeting 2016 in New Orleans, LA.

Using the company’s MammaPrint® assay, patients with early-stage breast cancer who were considered at high risk for disease recurrence based on clinical and biological criteria had a distant metastasis-free survival at five years in excess of 94 percent.The MammaPrint test—the first and only genomic assay with FDA 510(k) clearance for use in risk assessment for women of all ages with early stage breast cancer—identified a large group of patients for whom five-year distant metastasis–free survival was equally good whether or not they received adjuvant chemotherapy (chemotherapy given post-surgery).

“The MINDACT trial design is the optimal way to prove clinical utility of a genomic assay,” said Prof. Laura van ’t Veer, CRO at Agendia, Leader, Breast Oncology Program, and Director, Applied Genomics at UCSF Helen Diller Family Comprehensive Cancer Center. “It gives the level 1A clinical evidence (prospective, randomized and controlled) that empowers physicians to clearly and confidently know when chemotherapy is part of optimal early-stage breast cancer therapy.  In this trial, MammaPrint (70-gene assay) was compared to the standard of care physicians use today, to decide what is the best treatment option for an early-stage breast cancer patient.”

The MINDACT trial is the first prospective randomized controlled clinical trial of a breast cancer recurrence genomic assay with level 1A clinical evidence and the first prospective translational research study of this magnitude in breast cancer to report the results of its primary objective.

Among the 3,356 patients enrolled in the MINDACT trial, who were categorized as having a high risk of breast cancer recurrence based on common clinical and pathological criteria (C-high), the MammaPrint assay reduced the chemotherapy treatment prescription by 46 percent.Using the 70-gene assay, MammaPrint, 48 percent of lymph-node positive breast cancer patients considered clinically high-risk (Clinical-high) and genomic low-risk (MammaPrint-low) had an excellent distant metastasis-free survival at five years in excess of 94 percent.

“Traditionally, physicians have relied on clinical-pathological factors such as age, tumor size, tumor grade, lymph node involvement, and hormone receptor status to make breast cancer treatment decisions,” said Massimo Cristofanilli, MD, Associate Director of Translational Research and Precision Medicine at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University in Chicago. “These findings provide level 1A clinical utility evidence by demonstrating that the detection of low-risk of distant recurrence reported by the MammaPrint test can be safely used in the management of thousands of women by identifying those who can be spared from a toxic and unnecessary treatment.”

MINDACT is a randomized phase III trial that investigates the clinical utility of MammaPrint, when compared (or – “used in conjunction with”) to the standard clinical pathological criteria, for the selection of patients unlikely to benefit from adjuvant chemotherapy. From 2007 to 2011, 6,693 women who had undergone surgery for early-stage breast cancer enrolled in the trial (111 centers in nine countries). Participants were categorized as low or high risk for tumor recurrence in two ways: first, through analysis of tumor tissue using MammaPrint at a central location in Amsterdam; and second, using Adjuvant! Online, a tool that calculates risk of breast cancer recurrence based on common clinical and biological criteria.

Patients characterized in both clinical and genomic assessments as “low- risk” are spared chemotherapy, while patients characterized as “high- risk” are advised chemotherapy. Those with conflicting results are randomized to use either clinical or genomic risk (MammaPrint) evaluation to decide on chemotherapy treatment.

The MINDACT trial is managed and sponsored by the EORTC as part of an extensive and complex partnership in collaboration with Agendia and BIG, and many other academic and commercial partners, as well as patient advocates.

“These MINDACT trial results are a testament that the science of the MammaPrint test is the most robust in the genomic breast recurrence assay market.  Agendia will continue to collaborate with pharmaceutical companies, leading cancer centers and academic groups on additional clinical research and in the pursuit of bringing more effective, individualized treatments within reach of cancer patients,” said Mark Straley, Chief Executive Officer at Agendia. “We value the partnership with the EORTC and BIG and it’s a great honor to share this critical milestone.”

Breast cancer is the most frequently diagnosed cancer in women worldwide(1). In 2012, there were nearly 1.7 million new breast cancer cases among women worldwide, accounting for 25 percent of all new cancer cases in women(2).

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Neoadjuvant Therapy for Breast Cancer

Larry H. Bernstein, MD, FCAP, Curator



Neoadjuvant Therapy for Early-Stage Breast Cancer: Current Practice, Controversies, and Future Directions

Review ArticleNovember 15, 2015Oncology Journal, Breast Cancer

Breast evaluation

Locoregional assessment should be performed with careful physical examination and the use of mammography and ultrasound as recommended by the National Comprehensive Cancer Network (NCCN) guidelines.[9,14] Magnetic resonance imaging (MRI) of the breast is more sensitive in determining the extent of the tumor but it may also overestimate the tumor size.[15] MRI may be performed if there are other areas of concern on initial imaging that may warrant additional evaluation.[16] A baseline MRI has been shown to decrease re-excision rates, and this procedure also allows for assessment of the contralateral breast, where there is a 3% to 10% likelihood of synchronous disease.[17,18] The decision to pursue an MRI should be tailored to each patient’s specific clinical situation and needs, particularly if BCS is desired.


According to NCCN guidelines, image-guided core needle biopsy with placement of an image-detectable marker of the breast abnormality is necessary to confirm the diagnosis; provide tissue to assess pathologic markers, including ER, progesterone receptor (PR), and HER2 status; and demarcate the tumor bed for post-neoadjuvant management.[9] Tumor grade and Ki-67 levels may also be assessed, as these may estimate a more aggressive phenotype and may predict response to chemotherapy. Other testing on tissue obtained by core needle biopsy, such as Oncotype DX or other commercial genotyping, is not a standard of care in the preoperative setting at this time and should not be obtained routinely outside the context of a clinical trial. Many biomarkers are currently under development, including tumor-infiltrating lymphocytes (TILs), which have been associated with higher likelihood of pCR in HER2-positive disease and TNBC, and the homologous recombination deficiency score, which has been found to be an excellent predictor of pCR in patients with TNBC receiving platinum-based neoadjuvant chemotherapy.[19-21]


Axillary evaluation

Patients being considered for neoadjuvant chemotherapy should undergo careful physical examination of the axilla and review of mammography and ultrasonography.[16] If the clinical or breast imaging results are notable for lymphadenopathy, a dedicated axillary ultrasound is recommended for further evaluation. Fine needle aspiration (FNA) or core needle biopsy should be performed on any suspicious-appearing lymph nodes (Figure). Core needle biopsy is more accurate, particularly in invasive lobular carcinomas, and when feasible, it may be preferred to FNA; either procedure is acceptable, however, according to the NCCN guidelines.[9,22] The placement of a biopsy clip should be strongly considered when performing an FNA or core needle biopsy, because use of the clip can improve the rate of successful surgical resection of biopsy-proven metastatic axillary lymph nodes. This allows for more accurate assessment of pathologic response in the axilla, and decreases the false-negative rate when performing a sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy in patients with known axillary nodal involvement prior to systemic treatment.[23,24]


For patients with clinically node-negative breast cancer at diagnosis, the role of performing an SLNB prior to or following neoadjuvant chemotherapy is controversial. In the SENTINA study, 35% of clinically node-negative patients were found to have pathologically node-positive disease on SLNB performed prior to neoadjuvant chemotherapy.[25] Among these patients, repeat SLNB after neoadjuvant chemotherapy detected additional sentinel lymph nodes (SLNs) in 61% of patients, with a high false-negative rate of 51.6%. Thus, SLNB performed after excision of a positive node prior to neoadjuvant therapy has poor reliability.


In another study, compared with the same procedure performed prior to treatment, SLNB following neoadjuvant chemotherapy resulted not only in lower SLN identification rates (98% vs 95%, before vs after neoadjuvant therapy, respectively; P = .032), but also in less frequent axillary dissections or radiation (45% vs 33%; P = .006); therefore, performing an SLNB after neoadjuvant therapy potentially reduced morbidity.[26] Furthermore, one key limitation of SLNB prior to neoadjuvant therapy is that removal of affected nodes prior to treatment precludes the ability to assess pathologic response and decreases the significance of achieving a pCR.[27] Given that compelling data on routine SLNB before neoadjuvant therapy are lacking, our preference is to perform SLNB after neoadjuvant therapy in patients with a clinically node-negative axilla at presentation; however, patient management in this setting must be individualized.


Evaluation of distant disease

Patients with stage I and II disease who are asymptomatic at presentation do not require routine systemic imaging; however, patients with stage III disease should be considered for systemic imaging even in the absence of symptoms, since they are at higher risk for harboring systemic disease.[9] According to NCCN guidelines, however, routine systemic imaging in the absence of symptoms is not indicated, but any patient experiencing systemic symptoms should undergo laboratory testing and systemic staging as indicated.[9] Nuclear bone scan and computed tomography (CT) scans with contrast of the chest, abdomen, and pelvis can adequately assess for systemic disease, and should be considered as a first step unless a contraindication exists. Additional imaging, including positron emission tomography (PET) scans and MRI, may be required in select cases. Areas suspicious for distant metastasis should undergo biopsy to confirm metastatic disease. Patients with central nervous system symptoms should undergo brain MRI.


Benefits and indications

Historically, the primary indication for neoadjuvant therapy has been to facilitate breast surgery (see Table).[2] Neoadjuvant chemotherapy has the potential to convert unresectable tumors to resectable ones, and can reduce the extent of surgery needed to achieve adequate resection. For patients with inflammatory breast cancer, neoadjuvant therapy is considered a standard of care (unless a contraindication exists) and may confer a survival benefit in this population.[3] If patients are not candidates for surgery at the time of diagnosis, neoadjuvant therapy can be used as a bridge to operability in selected cases. Similarly, patients who want to undergo breast-conserving surgery (BCS) but are not candidates for this approach at diagnosis may also be considered for neoadjuvant therapy; among such patients, BCS rates as high as 72.3% (odds ratio [OR], 1.7 [95% confidence interval (CI), 1.6–1.8]) have been reported.[4,5]


There are many other instances when neoadjuvant therapy may be considered (see Table). For example, patients with chemoresponsive breast cancers may benefit from this treatment. Of all clinical breast cancer subtypes, human epidermal growth factor receptor (HER) 2–positive breast cancer and triple-negative breast cancer (TNBC) are the most chemosensitive, and therefore are most amenable to neoadjuvant chemotherapy; indeed, patients with HER2-positive disease and TNBC have the highest pathologic complete response (pCR) rates.[6] Patients with aggressive estrogen receptor (ER)-positive breast cancer subtypes, or luminal B–like phenotype breast cancers, tend to have higher pCR rates than those with more indolent ER-positive subtypes (pCR, 15% vs 7.5%), and so may be more suitable for neoadjuvant therapy.[7] Patients with classic invasive lobular breast cancer tend to have inferior responses to neoadjuvant chemotherapy compared with those who have invasive ductal carcinomas (pCR, 11% vs 25%; P = .01), and are therefore less likely to benefit from neoadjuvant chemotherapy.[8] In patients with node-positive disease, for which chemotherapy is the standard of care regardless of the sequencing of drug administration, response to neoadjuvant treatment has a potential impact on locoregional management, including the extent of axillary surgery and the radiation targets selected. In clinical research trials, the neoadjuvant setting is useful for evaluation of the biologic and clinical effects of novel agents, and is thus a powerful research tool. Importantly, because tissue is readily available both before and after therapy in this setting, investigation of tissue-based biomarkers is logistically more feasible.



Neoadjuvant chemotherapy is not recommended routinely for patients with stage I breast cancer[9]—particularly if it is unclear whether to administer chemotherapy, or when third-generation vs first- or second-generation chemotherapy regimens are being considered. In these cases, the final surgical pathology report is often essential to making decisions about the need for chemotherapy and the type of regimen. The extent of tumor as defined by focality may affect BCS rates after neoadjuvant chemotherapy, when multifocal or multicentric tumors have lower chances of achieving eligibility for BCS (unifocal, 71.6%; multifocal, 58.5%; multicentric, 30%).[10] Rates of pCR may also differ slightly depending on tumor focality (unifocal, 19.4%; multifocal, 16.5%; multicentric, 14.4%). Patients with multicentric rather than unifocal tumors may have inferior DFS (P < .001) and OS (P < .009) after neoadjuvant chemotherapy; however, this disadvantage is abrogated if pCR is achieved.[10]


There are insufficient data to support use of BCS after neoadjuvant chemotherapy in multicentric or multifocal disease; therefore, cases should be considered on an individual basis.[2] For patients with multicentric disease (ie, multiple tumors in different quadrants of the breast) at presentation, mastectomy would be the standard of care regardless of response to neoadjuvant therapy. If multifocal disease (ie, multiple distinct tumors in the same quadrant of the breast) is present, BCS may become possible. It is important to bear in mind, however, that although the individual lesions may decrease in size in response to neoadjuvant therapy, the distance between lesions remains the same.


Progression during neoadjuvant chemotherapy is uncommon. While most patients are still able to undergo surgery, studies have reported that up to 12% of patients who started neoadjuvant chemotherapy were not able to undergo definitive surgery.[11] Even more uncommon, distant metastasis has been described in 4% of patients who experience disease progression while receiving neoadjuvant chemotherapy.[11] Factors that predict progression of disease during neoadjuvant therapy include African-American race, advanced tumor stage, high nuclear grade, high Ki-67 levels, and hormone receptor negativity.[12] Patients with breast cancer subtypes that are relatively less chemosensitive, such as luminal A or classic invasive lobular breast cancer, may also be less likely to benefit from neoadjuvant therapy.[7,8] These data underscore the importance of careful patient selection and monitoring during treatment.


In the neoadjuvant setting, therapeutic decisions are largely based on clinical staging; this includes physical examination and results obtained with imaging modalities, which may be less accurate than surgical staging. Nodal staging, in particular, may affect radiation therapy options.[13]



Additional considerations

The treatment of breast cancer requires a multidisciplinary approach. Although initial evaluation may be performed by a surgical or medical oncologist, there are several additional factors that should be considered during the initial assessment. In complex cases, the use of a multidisciplinary tumor board, in which pathologists; radiologists; and surgical, medical, and radiation oncologists review the case, can facilitate the development of a treatment strategy. An early referral to radiation oncology as part of the initial assessment should be recommended, particularly when clinical trials are available or there are questions of disease burden, since response to treatment may impact radiation planning. Early involvement of plastic surgery can aid in surgical planning, particularly as it may pertain to cosmetic outcomes. Genetic counseling early in the process can also be helpful, since this may inform final surgical treatment decisions. In cases of patients whose subsequent cancer risk is affected by hereditary mutations, such as BRCA1 or BRCA2, the decision to perform mastectomy and/or prophylactic mastectomy may be considered. In addition, the neoadjuvant setting also provides numerous opportunities for research and clinical trial participation, and these opportunities should be discussed with all eligible patients.


Research in the fields of surgical, medical, and radiation oncology has changed the landscape of neoadjuvant therapy in breast cancer, yet many areas of controversy still exist. When considering whether a patient is a candidate for neoadjuvant therapy, ideally the initial assessment should be multidisciplinary in nature and should include clinical, radiographic, and pathologic evaluation. Optimization of systemic therapy is dependent upon identifying the patient’s breast cancer subtype; the best approach may include targeted agents, as well as the determination of eligibility for enrollment into clinical trials that incorporate novel therapeutics or predictive biomarkers. This article will review a variety of surgical and radiation-based strategies for management of early-stage breast cancer, including surgical options involving the breast and axilla, and the role of radiation based on response to systemic therapy. Key areas of controversy include the ideal systemic treatment for different breast cancer subtypes, the surgical and radiotherapeutic approaches for management of the axilla, and the role of pathologic response rates as a surrogate for survival in drug development.


Hormone receptor (HR)-positive breast cancer

Unless in the context of a clinical trial, patients with aggressive phenotype HR-positive breast cancer who are candidates for chemotherapy should be treated with neoadjuvant chemotherapy rather than endocrine therapy, since compared with indolent HR-positive subtypes they have superior rates of response.[7] There are data, however, that suggest that neoadjuvant endocrine therapy may be effective. Studies comparing neoadjuvant endocrine therapy with chemotherapy have shown similar clinical response rates (48% to 67% vs 63% to 66%, respectively), and pCR rates were comparable but low (0% to 3% vs 1% to 6%, respectively).[28,29] Of note, the majority of patients included in these studies had ER and PR positivity and had grade 1/2 histology, suggesting that these may be less aggressive in nature and more likely to be sensitive to endocrine therapy. Since these studies demonstrated low pCR rates with chemotherapy in HR-positive breast cancer, primary surgery should be considered, unless there is an indication for neoadjuvant therapy. Several studies investigating neoadjuvant aromatase inhibitors (AIs) vs tamoxifen have also been conducted, demonstrating either equal efficacy or superiority of AIs, with clinical response rates ranging from 38% to 70% for AIs and 36% to 51% for tamoxifen.[30-33] In a phase II study comparing different AIs, clinical response rates were highest with letrozole (74.8% [95% CI, 66.3–82.1]) and anastrozole (69.1% [95% CI, 60.1–77.1]), and lowest with exemestane (62.9% [95% CI, 53.8–71.4]); however, future studies are needed to definitively demonstrate that one AI is superior to another.[34] The duration of therapy is also an important factor, with several studies suggesting treatment duration in excess of 3 to 4 months is optimal.[35-37] In patients who are unable to undergo surgery or receive chemotherapy, neoadjuvant endocrine therapy may be an appropriate alternative. Assays that reflect tumor biology may be useful in determining who is a good candidate for neoadjuvant chemotherapy vs hormonal therapy.




Figure: Algorithm Describing Approach to Neoadjuvant Therapy



HER2-positive breast cancer

The addition of the anti-HER2 monoclonal antibody trastuzumab to chemotherapy has resulted in an increase in pCR rates, from 20% to 43% (relative risk [RR], 2.07 [95% CI, 1.41–3.03]; P = .0002), and a decreased relapse rate, from 20% to 12% (RR, 0.67 [95% CI, 0.48–0.94]).[38] Furthermore, event-free survival (EFS) and OS benefits (hazard ratio [HR], 0.64; P = .016 and HR, 0.66; P = .055, respectively) have been demonstrated in the NOAH study, which was presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.[39]

The success of lapatinib, a tyrosine kinase inhibitor (TKI) targeting the intracellular domain of HER2, in the metastatic setting motivated several studies investigating this drug in the neoadjuvant setting. Investigators from the European Organisation for Research and Treatment of Cancer (EORTC) 10054 study, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 study, the Cancer and Leukemia Group B (CALGB) 40601 study, and the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) study reported that the addition of lapatinib to trastuzumab-based neoadjuvant chemotherapy improved pCR rates by 4% to 21%.[40-43] NeoALTTO randomized patients to paclitaxel and either lapatinib, trastuzumab, or a combination of lapatinib and trastuzumab. Following completion of chemotherapy, the patients underwent definitive surgical treatment and then received adjuvant anthracycline-based chemotherapy. While this study demonstrated a striking improvement in pCR rate with the addition of lapatinib to trastuzumab (pCR, 30% for the trastuzumab arm vs 51% for the trastuzumab/lapatinib arm), combination treatment was not associated with improved EFS (HR, 0.78 [95% CI, 0.47–1.28]; P = .33) or OS (HR, 0.62 [95% CI, 0.30–1.25]; P = .19). The study was not powered to detect small differences in survival outcomes, however.

The confirmatory Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study, presented at the 2014 ASCO Annual Meeting, failed to demonstrate that adding lapatinib to trastuzumab-based chemotherapy improves DFS (HR, 0.84 [95% CI, 0.70–1.02]; P = .048, with P ≤ .025 needed to achieve statistical significance).[44] The discordant results between NeoALTTO and ALTTO may be explained in part by the timing of the anthracycline-based therapy, since in NeoALTTO this regimen was given after surgery, and therefore did not have an impact on pCR rates. The findings inform future study designs, suggesting that all chemotherapy should be given upfront before surgery. Given that there is no survival benefit to adding lapatinib to neoadjuvant trastuzumab-based chemotherapy, at this time it is not considered a standard of care for patients with early HER2-positive breast cancer, and should not be routinely prescribed except in the context of a clinical trial.

Pertuzumab is a monoclonal antibody against HER2 and HER3. It has demonstrated a survival benefit for patients with metastatic HER2-positive breast cancer, and has also been studied in the neoadjuvant setting.[45] The NeoSphere trial found that the addition of pertuzumab to trastuzumab and docetaxel improved pCR rates from 29% to 45.8%.[46] A recent update reported at the 2015 ASCO Annual Meeting suggested a trend for improved DFS, but this was not statistically significant (HR, 0.60 [95% CI, 0.28–1.27]).[47] The TRYPHAENA study compared a combination regimen of pertuzumab, trastuzumab, docetaxel, and carboplatin vs two other pertuzumab-based regimens (both including epirubicin), and showed an unprecedented pCR rate of 66.2% in the non–anthracycline-containing arm.[48] Based on the results of NeoSphere and TRYPHAENA, the US Food and Drug Administration (FDA) granted approval for the use of pertuzumab in the neoadjuvant setting.

The results of the APHINITY study will confirm whether the addition of pertuzumab improves survival outcomes in early HER2-positive breast cancer. Until then, the strict approval for use of pertuzumab in early breast cancer remains in the neoadjuvant setting, but the NCCN guidelines have made provisional statements to also consider its use in the adjuvant setting.[9] The success of several novel therapeutics in the metastatic setting has led to studies in the neoadjuvant setting. The effects of neoadjuvant trastuzumab emtansine (T-DM1) with or without hormone therapy in HR-positive, HER2-positive early breast cancer were reported at the 2015 ASCO Annual Meeting. Compared with trastuzumab administered with endocrine therapy, pCR rates were substantially higher in the T-DM1 arms (6.7% vs 40.5% and 45.8%, respectively; P < .001).[49] The novel TKI neratinib, which irreversibly inhibits HER2, was studied in the I-SPY 2 trial, in which it demonstrated overall pCR rates of 32% (95% CI, 28–36); a larger registration trial is planned.[50]



Triple-negative breast cancer

Although there are no approved drugs specifically indicated for TNBC, this subtype is associated with relatively high pCR rates following chemotherapy, with many novel agents under investigation. The addition of the anti–vascular endothelial growth factor receptor (VEGFR) monoclonal antibody bevacizumab to chemotherapy has been studied extensively in the setting of neoadjuvant treatment for breast cancer. The German Breast Group (GBG) 44 study and the Avastin Randomized Trial With Neoadjuvant Chemotherapy for Patients With Early Breast Cancer (ARTemis) found that in TNBC cohorts, the addition of bevacizumab improved the rates of ypT0N0 pCR by 11.4% (P = .003) and 14% (P = .03), respectively.[51,52] The recently presented Austrian Breast and Colorectal Cancer Study Group (ABCSG) 32 study and the Southwestern Oncology Group (SWOG) S0800 study have also reported improvements in pCR rates, especially in patients with TNBC.[53,54] The NSABP B-40 and CALGB 40603 studies found statistically significant improvements in ypT0Nx pCR in the breast with the addition of bevacizumab, but differences in ypT0N0 rates were not statistically significant (P = .08 and P = .057, respectively).[55,56] While these neoadjuvant studies demonstrated improvements in pCR, three large randomized studies in multiple breast cancer subtypes in the adjuvant setting have failed to demonstrate a survival advantage.[57-59] These data demonstrate no role for bevacizumab at this time in unselected populations with early-stage breast cancer.

Platinum agents such as carboplatin have been investigated in the neoadjuvant setting—administered at different dosing schedules and in a variety of combinations with other agents—and have consistently been shown to improve pCR rates. The CALGB 40603 study found rates of ypT0N0 pCR improved from 41% to 54% (P = .0029); in GeparSixto, pCR rates in the TNBC cohort improved from 36.9% to 53.2% (P = .005); and in the I-SPY 2 study reported at the 2013 San Antonio Breast Cancer Symposium, the estimated pCR rate with carboplatin/veliparib was 52%.[55,59,60] Notably, these studies used various doses and schedules of carboplatin, and in combinations with non–standard-of-care agents such as bevacizumab and veliparib. The addition of carboplatin is associated with significant myelosuppression and nausea. Grade 3/4 hematologic adverse events ranged from 59% to 82% in the GeparSixto study.[59] In the CALGB 40603 study, patients who received carboplatin were more likely to miss more than two doses of paclitaxel (36% vs 16%). Additionally, 20% of patients did not receive all planned doses of anthracyclines and taxanes, and many required dose reductions.[55] This is an important factor to consider, since long-term survival data for anthracyclines and taxanes are robust.[61] In summary, given the significant toxicity of carboplatin, its incorporation into the neoadjuvant management of breast cancer requires additional studies, which should use consistent doses and schedules of carboplatin, integrate it into standard treatment regimens, and provide long-term survival data. Furthermore, adjuvant studies have been initiated to study the benefit of adding platinum drugs to treatment regimens for early-stage TNBC.

Residual disease

Patients treated with neoadjuvant chemotherapy who have residual disease at the end of treatment are at increased risk of recurrence. This relationship is particularly true of patients with TNBC (DFS HR, 6.02 [95% CI, 3.92–9.25]; P < .001), HER2-positive disease (DFS HR, 8.74 [95% CI, 3.17–24.12]; P < .001), and luminal B breast cancer (DFS HR, 5.95 [95% CI, 1.46–24.25]; P = .013).[62] Because of the complexities of assessing pathologic characteristics of residual disease, the Breast International Group and the North American Breast Cancer Group have set forth guidelines that focus on a multidisciplinary approach, rigorous pathologic sampling, use of biopsy clips, and the consideration of receptor retesting when it may affect clinical management (ie, patients with initial receptor-negative status).[27]

Receptor status has been demonstrated to change with neoadjuvant chemotherapy, and may be associated with prognosis when there is loss of the ER.[63] In one series examining receptor status after neoadjuvant therapy, 10.3% of patients with tumors that were ER-positive and HER2-negative on core needle biopsy became ER-negative on excision, whereas 34.5% of patients with TNBC on core needle biopsy became ER-positive at the time of surgical resection. This study is limited because it did not report the change in percentage of ER labeling in tumors with discordant ER status results, and the differences may reflect tumor heterogeneity, tissue sampling, or technical issues with the assays. Nevertheless, changes did correspond with outcomes, as patients whose tumors were ER-negative on excision had inferior recurrence-free survival (RFS; HR, 3.54 [95% CI, 1.60–7.85]), while patients whose tumors became ER-positive had a trend toward improved RFS (HR, 1.32 [95% CI, 0.64–2.74]).[63]

In addition to standard American Joint Committee on Cancer/Union for International Cancer Control TNM staging, the Residual Cancer Burden (RCB) system can be used for patients who have residual disease. The RCB system incorporates not only residual disease, but also the primary tumor size and nodal burden, and it can be used to determine the risk of recurrence.[64] Biomarkers are under development to further characterize patients with residual disease after neoadjuvant therapy. For instance, the presence of TILs has been found to be a favorable prognostic factor for metastasis-free survival and OS in patients with TNBC who have residual disease after neoadjuvant chemotherapy.[65] Furthermore, biomarkers such as multigene assays may be useful in the development of targeted therapies for patients with an increased risk of recurrence. Unfortunately, there is no standard additional therapy at this time for patients who have residual disease after neoadjuvant chemotherapy.

The KATHERINE study is investigating the role of T-DM1 in HER2-positive breast cancer with residual disease (ClinicalTrials.gov identifier: NCT01772472). For TNBC patients with residual disease, the role of cisplatin is being evaluated by investigators from the Eastern Cooperative Oncology Group (ECOG)/American College of Radiology Imaging Network (ACRIN) (ClinicalTrials.gov identifier: NCT02445391). A deeper molecular understanding of tumor biology is needed to help identify and overcome mechanisms of resistance to standard therapy.

Interpreting Pathologic Complete Response

For patients who achieve a pCR, numerous data demonstrate that they are more likely to experience a survival benefit when pCR is defined as ypT0/is ypN0.[66] Naturally, pCR achieved in a single patient may not correlate to the pCR rate in a population of patients as a function of a therapy. To date, only our experience with trastuzumab has demonstrated that improvements in pCR are linked to improved survival; investigations of lapatinib and bevacizumab have failed to show this, and we await results from the APHINITY trial to see if pertuzumab will demonstrate a correlation between pCR and survival endpoints.[39,44,58,59] Similarly, studies are ongoing in the neoadjuvant and adjuvant settings to investigate the role of carboplatin in early TNBC. Certainly the anticancer potency of the drug under investigation matters, and perhaps the degree of change in pCR rate may also matter. When considering neoadjuvant therapy, a clinician must weigh the potential benefits of agents with no proven survival benefit against their potential toxicity. The impact of toxicity on the ability of patients to complete standard-of-care therapy should also be considered. Furthermore, clinicians should be cautious in extrapolating neoadjuvant data to the adjuvant setting in the absence of survival data.

Surgical Considerations

Additional imaging following neoadjuvant therapy prior to surgery

In addition to clinical examination, imaging at the conclusion of neoadjuvant therapy can aid in the assessment of treatment response. Particularly when the patient desires BCS, critical to surgical decision making is the determination of whether neoadjuvant therapy has downstaged the tumor to the point where lumpectomy is feasible. MRI of the breast has been shown to be more accurate than mammography for evaluation of treatment response. Although the sensitivity of MRI is high (0.92), the specificity tends to be lower (0.6).[67] Correlation of MRI performed after neoadjuvant chemotherapy with pathology obtained from surgery has shown that MRI can both underestimate and overestimate pathologic size, although the discrepancy may be particularly related to HR-positive disease.[67-69] MRI alone, however, may not be adequate to assess for residual disease after neoadjuvant therapy. In one study, MRI alone correctly predicted suitability for BCS in 88% of patients, but MRI plus mammography improved this to 92%. Mammography after neoadjuvant therapy is important to assess the patient for extensive residual calcifications that may preclude BCS.[70] Close collaboration between surgery and radiology departments is crucial for assessing response to neoadjuvant therapy and surgical planning.

Partial vs complete mastectomy

Surgery after neoadjuvant therapy can be performed safely despite the potential toxicities associated with the therapy.[71] A primary objective of neoadjuvant therapy is to enhance surgical options for patients. One key measure of this is a decrease in mastectomy rate, and studies have found that mastectomies can be decreased by 16.6% to 27% after neoadjuvant therapy.[72,73] Interestingly, as pCR rates have increased with the use of modern neoadjuvant regimens, rates of BCS have not.[74,75] Reasons for this discrepancy may be related to tumor focality and centricity, patient preference, and residual ductal carcinoma in situ.[2] While, in general, BCS can be performed safely after neoadjuvant therapy, advanced nodal involvement, residual tumor > 2 cm, multifocal residual disease, and lymphovascular invasion predict higher rates of locoregional and ipsilateral breast tumor recurrence.[76]

Surgical axillary approach

The approach to initial evaluation of the axilla is discussed in an earlier section of this article. In women with clinically negative axillary lymph nodes, SLNB after neoadjuvant therapy yields similar identification rates compared with those of women who undergo primary surgery (97.4% vs 98.7%, respectively); recurrence rates are statistically similar as well (1.2% vs 0.9%, respectively).[77] Therefore, SLNB after neoadjuvant chemotherapy in patients with clinically negative lymph nodes at diagnosis is acceptable and considered to be the standard of care.[78] The role of SLNB vs axillary lymph node dissection in patients with clinically node-positive disease prior to neoadjuvant chemotherapy is more controversial. The American College of Surgeons Oncology Group (ACOSOG) Z1071 investigators found that in women with clinically node-positive breast cancer (cN1) who received neoadjuvant chemotherapy and then underwent SLNB, the false-negative rate was 12.6% (90% Bayesian credible interval, 9.85–16.05) when two or more SLNs were examined, and 9.1% (95% CI, 5.6–13.7) when three or more SLNs were examined; notably, in this study, false-negative rates > 10% were considered to be unacceptable.[79]

Additional analysis revealed that radiolabeled colloid alone or with blue dye, compared with blue dye alone, led to improved SLN identification rates.[80] The SENTINA study found that in women with clinically node-positive disease at diagnosis who converted to clinically node-negative status after neoadjuvant chemotherapy, SLNB following neoadjuvant chemotherapy resulted in a false-negative rate of 14.2% (95% CI, 9.9–19.4). If three or more lymph nodes were removed, the false-negative rate dropped to 7.3%, and the addition of blue dye to radiocolloid decreased the false-negative rate from 16% to 8.6%.[25] The Sentinel Node Biopsy Following Neoadjuvant Chemotherapy in Biopsy Proven Node Positive Breast Cancer (SN FNAC) study also found that increasing the number of SLNs removed decreased false-negative rates (with removal of one lymph node associated with a false-negative rate of 18.2% vs a rate of 4.9% for removal of two lymph nodes), as did mandatory use of immunohistochemistry and a broad definition of lymph node positivity with metastasis of any size, including isolated tumor cells.[81] While the NCCN guidelines state that axillary lymph node dissection should be performed in patients with clinically positive lymph nodes, the previously discussed data suggest that SLNB after neoadjuvant therapy is a feasible option for patients with initial node-positive disease when the procedure yields three or more lymph nodes, and dual radiotracer and dye techniques are used.[9] Alternative approaches are under investigation—for example, “targeted axillary dissection,” which includes SLNB in combination with targeted removal of biopsy-proven positive lymph nodes that were clipped at the time of initial core needle biopsy or FNA.[82] Furthermore, additional studies are needed to identify breast cancer subtypes for which patients with biopsy-proven nodal disease at presentation may derive the most benefit from SLNB after neoadjuvant therapy.

Radiation Considerations

For patients who undergo BCS after neoadjuvant therapy, radiation therapy to the breast is considered a standard of care whether or not pCR is achieved, as it is for patients who undergo upfront surgery.[9,83] For patients who undergo mastectomy, the roles of postmastectomy radiation therapy (PMRT) and regional nodal irradiation (RNI) are more controversial, particularly among those who achieve pCR. NCCN guidelines simply state that radiation therapy should be based on the worst stage either prior to or after neoadjuvant therapy.[9] Patients who have negative lymph nodes prior to and following neoadjuvant therapy generally do not require PMRT or RNI, and conversely those with residual node-positive disease are at higher risk of locoregional recurrence (LRR) and require PMRT/RNI.[84] However, studies evaluating the risk of LRR after neoadjuvant therapy have consistently demonstrated a lower risk of LRR in patients who achieve pCR compared with those who do not.[85-88] Subtype of breast cancer may additionally influence LRR rates in those achieving pCR, with TNBC generally associated with a higher LRR rate.[89] A pooled analysis of the NSABP B-18 and B-27 studies demonstrated low rates of LRR in patients with pCR who had mastectomy without PMRT; in these studies, the 10-year risk of LRR was < 10% in patients with pCR, regardless of initial nodal status or tumor size, suggesting that PMRT may not be needed in these patients.[87]

Conversely, a recent meta-analysis of patients treated in the German Gepar trials, presented at the 2015 ASCO Annual Meeting, found that among patients who achieved pCR, the use of PMRT was an independent prognostic factor for locoregional relapse–free survival (HR, 0.54 [95% CI, 0.035–0.82]; P = .004) and DFS (HR, 0.69 [95% CI, 0.51–0.93]; P = .016).[90] To address this conundrum, the Radiation Therapy Oncology Group (RTOG) and the NSABP have designed the randomized phase III NSABP B-51/RTOG 1304 trial (ClinicalTrials.gov identifier: NCT01872975) for patients who have positive axillary nodes before neoadjuvant chemotherapy but convert to pathologically negative axillary nodes. Patients will be randomized to PMRT with RNI vs no radiation in those who had mastectomy, and breast irradiation with or without RNI in those who have undergone BCS. This study will help to determine which patients can safely have PMRT and/or RNI omitted in the setting of nodal pCR.[91] In summary, at this time there are no prospective data to guide clinicians regarding use of radiation after neoadjuvant chemotherapy in the setting of pCR. Outside the setting of a clinical trial, the current NCCN guidelines recommend strong consideration of PMRT or RNI in patients who have positive lymph nodes either before or after neoadjuvant chemotherapy; treatment decisions should be made on a case-by-case basis (Figure).[84]


In carefully selected patients, neoadjuvant therapy can provide improved surgical outcomes, prognostic information, and access to clinical trials investigating novel agents and locoregional therapies. Management involves a multidisciplinary team that should include surgical, medical, and radiation oncologists; pathologists; radiologists; and, in certain cases, plastic surgeons, genetic counselors, and research staff. (A suggested algorithm, based on data presented in this review article, is provided in the Figure.) Since optimization of systemic and local therapies continues to be an evolving field, participation in a clinical trial should be considered for eligible patients.



1. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:188-94.

2. King TA, Morrow M. Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol. 2015;12:335-43.

3. Perez CA, Fields JN, Fracasso PM, et al. Management of locally advanced carcinoma of the breast. II. Inflammatory carcinoma. Cancer. 1994;74:466-76.

4. Barranger E, Antomarchi J, Chamorey E, et al. Effect of neoadjuvant chemotherapy on the surgical treatment of patients with locally advanced breast cancer requiring initial mastectomy. Clin Breast Cancer. 2015;15:e231-e235.

5. Killelea BK, Yang VQ, Mougalian S, et al. Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg. 2015;220:1063-9.

6. Connolly RM, Stearns V. Current approaches for neoadjuvant chemotherapy in breast cancer. Eur J Pharmacol. 2013;717:58-66.

7. Bonnefoi H, Litiere S, Piccart M, et al. Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial. Ann Oncol. 2014;25:1128-36.

8. Lips EH, Mukhtar RA, Yau C, et al. Lobular histology and response to neoadjuvant chemotherapy in invasive breast cancer. Breast Cancer Res Treat. 2012;136:35-43.

9. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33:13-21.

10. Ataseven B, Lederer B, Blohmer JU, et al. Impact of multifocal or multicentric disease on surgery and locoregional, distant and overall survival of 6,134 breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2015;22:1118-27.

…… more


Neoadjuvant Therapy for Early-Stage Breast Cancer: A Model for Individualizing Outcomes and Tailoring Locoregional and Systemic Therapy
Eleftherios P. Mamounas, MD, MPH
The biologic rationale for the initial evaluation of preoperative chemotherapy or neoadjuvant chemotherapy in patients with early-stage breast cancer was based on experimental and clinical observations regarding primary tumor cell growth and dissemination.
Neoadjuvant Therapy As a Platform for Drug Development: Current Controversies and Regulatory Perspectives
Laleh Amiri-Kordestani, MD, Julia A. Beaver, MD, and Patricia Cortazar, MD
This commentary addresses our perspectives from a regulatory standpoint, as well as some controversies related to the use of neoadjuvant therapy as a platform for drug development.


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Reporter: Ritu Saxena, Ph.D.

With the number of cancer cases plummeting every year, there is a dire need for finding a cure to wipe the disease out. A number of therapeutic drugs are currently in use, however, due to heterogeneity of the disease targeted therapy is required. An important criteria that needs to be addressed in this context is the –‘tumor response’ and how it could be predicted, thereby improving the selection of patients for cancer treatment. The issue of tumor response has been addressed in a recent editorial titled “Tumor response criteria: are they appropriate?” published recently in Future Oncology.

The article talks about how the early tumor treatment response methods came into practice and how we need to redefine and reassess the tumor response.

Defining ‘tumor response’ has always been a challenge

WHO defines a response to anticancer therapy as 50% or more reduction in the tumor size measured in two perpendicular diameters. It is based on the results of experiments performed by Moertel and Hanley in 1976 and later published by Miller et al in 1981. Twenty years later, in the year 2000, the US National Cancer Institute, with the European Association for Research and Treatment of Cancer, proposed ‘new response criteria’ for solid tumors; a replacement of 2D measurement with measurement of one dimen­sion was made. Tumor response was defined as a decrease in the largest tumor diameter by 30%, which would translate into a 50% decrease for a spherical lesion. However, response criteria have not been updated after that and there a structured standardization of treatment response is still required especially when several studies have revealed that the response of tumors to a therapy via imaging results from conventional approaches such as endoscopy, CT scan, is not reliable. The reason is that evaluating the size of tumor is just one part of the story and to get the complete picture inves­tigating and evaluating the tissue is essential to differentiate between treatment-related scar, fibrosis or micro­scopic residual tumor.

In clinical practice, treatment response is determined on the basis of well-established parameters obtained from diagnostic imaging, both cross-sectional and functional. In general, the response is classified as:

  • Complete remission: If a tumor disappears after a particular therapy,
  • Partial remission: there is residual tumor after therapy.

For a doctor examining the morphology of the tumor, complete remission might seem like good news, however, mission might not be complete yet! For example, in some cases, with regard to prognosis, patients with 0% residual tumor (complete tumor response) had the same prognosis com­pared with those patients with 1–10% residual tumor (subtotal response).

Another example is that in patients demonstrating complete remission of tumor response as observed with clinical, sonographic, functional (PET) and histopathological analysis experience recur­rence within the first 2 years of resection.

Adding complexity to the situation is the fact that the appropriate, clinically relevant timing of assess­ment of tumor response to treatment remains undefined. An example mentioned in the editorial is – for gastrointestinal (GI) malignancies, the assessment timing varies considerably from 3 to 6 weeks after initia­tion of neoadjuvant external beam radiation. Further, time could vary depending upon the type of radiation administered, i.e., if it is external beam, accelerated hyperfractionation, or brachytherapy.

Abovementioned examples remind us of the intricacy and enigma of tumor biol­ogy and subsequent tumor response.


Owing to the extraordinary het­erogeneity of cancers between patients, and pri­mary and metastatic tumors in the same patients, it is important to consider several factors while determining the response of tumors to different therapie in clinical trials. Authors exclaim, “We must change the tools we use to assess tumor response. The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ charac­teristics.”

Future perspective

Editorial points out that the oncologists, radiotherapists, and immunologists all might have a different opinion and observation as far as tumor response is considered. For example, surgical oncologists might determine a treatment to be effective if the local tumor control is much better after multimodal treatment, and that patients post-therapeutically also reveal an increase of the rate of microscopic and macroscopic R0-resection. Immunologists, on the other hand, might just declare a response if immune-competent cells have been decreased and, possibly, without clinical signs of decrease of tumor size.

What might be the answer to the complexity to reading tumor response is stated in the editorial – “an interdisciplinary initiative with all key stake­holders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prog­nosis.”


Editorial : Björn LDM Brücher et al Tumor response criteria: are they appropriate? Future Oncology August 2012, Vol. 8, No. 8, 903-906.

Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981, 47(1),207–214.

Related articles to this subject on this Open Access Online Scientific Journal:

See comment written for :

Knowing the tumor’s size and location, could we target treatment to THE ROI by applying

http://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-target-treatment-to-the-roi-by-applying-imaging-guided-intervention/imaging-guided intervention?

Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)


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