Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC):
  • Is an individual patient data analysis intended to evaluate the role of chemotherapy in head and neck cancers
  • It is known for its rigorous process for quality data collection and its large ongoing data- base
  • Results of indirect comparisons were not limited to evaluation of survival advantage:
    • But an estimate of the interaction between the treatment effects and the timing of chemotherapy as adjuvant, concurrent, neoadjuvant, or induction was made possible (Pignon and Bourhis, 1995 Oct)
  • Since the first reports of MACH-NC:
    • Results demonstrated an:
      • 8.6% benefit of cause-specific survival (CSS) at 5 years, hazard ratio, 0.81; 95% CI, 0.78–0.86; P = 0.001):
        • For concurrent chemoradiation (CCRT):
          • While systemic chemotherapy in the setting of induction or adjuvant did not show OS advantage
      • Nevertheless, the magnitude of the overall response rate of induction chemotherapy (IC) with the PF regimen (cisplatin 100 mg/m2 on day 1 and 5-fluorouracil 1000 mg/m2 daily for 5 days):
        • Was high and ranged from 57% to 80%, with a complete response rate of 19% to 48%
      • Analyses on the subset of 15 trials who received PF:
        • Showed a modest improvement in OS compared to CCRT (HR, 0.90; 95% CI, 0.82–0.99):
          • Which is a survival gain equal to 5% at 5 years
      • In the MACH-NC a subset analysis of 16 IC trials with non-PF combinations:
        • Did not show survival benefit with these IC regimens:
          • Which is attributed to the low dose of ineffective regimens that were administered for a duration not long enough:
            • Here, PF showed more adequate responses in comparison with non-PF trials:
              • Which reflects the nature of PF as a more potent drug combination for the most common administered schedules (Pignon et al., 2009; Monnerat et al., 2002):
                • So, in particular PF became the dominant induction regimen for years

• The standard of care with respect to surgical management of early stage breast cancer with a clinically negative axilla:
  • Is to undergo axillary staging with sentinel lymph node biopsy (SLNB)
• In patients who are clinically node negative undergoing lumpectomy with SLNM and SLNB:
  • A completion axillary lymph node dissection (ALND) is not required if one or two lymph nodes are positive:
    • These patients should go on to receive adjuvant therapy:
      • Omission of ALND does not lead to a difference in 10-year locoregional recurrence or overall survival
  • There is, however, a role for omission of axillary staging in elderly women:
    • Who are clinically node negative with ER+ tumors:
      • Particularly if co-morbidities are present
  • The Cancer and Leukemia Group B (CALBG) 9343 study:
    • Evaluated women ≥ 70 years of age who underwent lumpectomy:
      • For clinical T1, N0, ER+ breast cancer +/- adjuvant radiation (RT):
        • With tamoxifen (Tam) recommended for all patients
    • Of the 636 participants:
      • 404 (64%) did not undergo any initial axillary surgery
    • At 12-year follow-up:
      • There were no axillary recurrences among women who underwent initial axillary dissection
      • Among those who did not undergo axillary dissection:
        • There were no axillary recurrences:
          • In the Tam + RT group
        • Six of 200 in the Tam group (3%) had axillary recurrences
  • The International Breast Cancer Study Group Trial 10-93:
    • Evaluated 473 patients with early stage breast cancer who were clinically node negative
    • Patients had a mean age of 74
    • The majority of patients were ER+, and patients were randomized to breast surgery +/- axillary dissection followed by endocrine therapy
    • Overall, 2% of patients had an axillary recurrence (1% of those with axillary surgery vs. 3% in patients without axillary surgery):
      • With no difference in disease-free and overall survival.
• Results from these and other studies recently led the Society of Surgical Oncology to release the Choosing Wisely guidelines:
  • Recommending against routine use of SLNB in clinically node-negative women ≥70 years of age with hormone positive cancer:
  • Hormonal therapy is typically recommended for patients with hormone receptor positive disease
  • Omission of SLNB in clinically node-negative women ≥70 years of age treated with hormonal therapy does not result in a significantly increased rate of locoregional recurrence and does not impact breast cancer mortality:
    • Thus, although axillary staging with SLNB continues to be the standard of care:
      • Omission of axillary staging can be considered in some patients ≥70 years of age with:
        • Early stage, clinically node-negative, hormone receptor positive breast cancer
• References
  • Giuliano AE, Ballman K, McCall L, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 randomized trial. Ann Surg. 2016;264(3):413-420.
  • Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA. 2017;318(10):918-926.
  • Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-2387.
  • International Breast Cancer Study Group: Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93. J Clin Oncol.2006;24(3):337-344.
  • Society of Surgical Oncology. Five things physicians and patients should question. Choosing Wisely website. Released July 12, 2016; updated June 20, 2019. http://www.choosingwisely.org/societies/society-of-surgical-oncology. Accessed August 25, 2019.

• The most common advérese events (AE) observed in the olaparib arm during the OlympiA trial were:
  • Nausea, fatigue, anemia, and vomiting:
    • Most of which were of grade 1 or 2
• At the updated analysis, no new safety signals were detected (including no new cases of acute myeloid leukemia or myelodysplastic syndrome)

• Hormone receptor–positive, HER2 negative:
  • Is the most common breast cancer subtype
• Endocrine therapy (used alone or in combination):
  • Has been a longstanding standard of care for hormone receptor–positive breast cancer:
    • In both the early and advanced stages
• In more recent years, endocrine therapy combined with a CDK4/6 inhibitor:
  • Has become the first-line standard of care for most women with hormone receptor–positive, HER2 negative metastatic breast cancer (MBC)
• Use of first-line endocrine therapy plus a CDK4/6 inhibitor is based on positive results from several clinical trials:
  • The hazard ratios for progression-free survival (PFS) were very similar in these trials
• Recently, statistically significant improvements in overall survival were reported in multiple phase 3 studies of ribociclib plus endocrine therapy:
  • For example, the secondary end point of overall survival (OS) was met in the MONALEESA-2 study of ribociclib plus an aromatase inhibitor
  • Of note, at the second interim analysis of data from the phase 3 MONARCH-3 clinical trial of abemaciclib plus endocrine therapy, OS data remained immature (HR, 0.754; 95% CI, 0.584-0.974; P = 0.03)
  • The addition of palbociclib to letrozole in the PALOMA-2 study of did not yield a statistically significant benefit in terms of OS (HR, 0.956; 95% CI, 0.777–1.177):
    • PALOMA-2 study investigators noted that final OS data were missing for 13% in the experimental arm vs 21% in the control arm

• The safety and efficacy of olaparib as adjuvant therapy was evaluated in the phase 3 OlympiA trial:
  • That enrolled patients with a germline BRCA mutation and HER2-, high-risk, early-stage breast cancer who had completed definitive local treatment and at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, a taxane, or both (prior platinum for previous cancer or as adjuvant /neoadjuvant breast cancer treatment was permitted)
• Patients were randomly assigned (1:1) to receive:
  • Olaparib tablets 300 mg orally twice daily or placebo
• Treatment was continued for up to 1 year or until disease recurrence or unacceptable toxicity occurred
• In this study, patients with high-risk, early breast cancer were identified using the following criteria: 
  • Patients who received prior neoadjuvant chemotherapy:
    • Triple-negative breast cancer (TNBC):
      • They needed to have residual invasive cancer in the breast and / or the resected lymph nodes (nonpathologic complete response) at the time of surgery
    • Hormone receptor–positive breast cancer:
      • They needed to have residual invasive cancer in the breast and / or the resected lymph nodes (nonpathologic complete response) at the time of surgery:
        • Additionally, they needed a score of 3 or more based on pretreatment clinical and post-treatment pathologic stage, ER status, and histologic grade (Table)
  • Patients who received prior adjuvant chemotherapy:
    • TNBC:
      • They needed to have node-positive disease or node-negative disease with the primary tumor measuring 2 cm or more
    • Hormone receptor–positive, HER2- breast cancer:
      • They needed to have 4 or more pathologically-confirmed positive lymph nodes

• Updated results, representing a median follow up of 3.5 years, were published in October 2022:
  • A significant improvement in OS was observed in the olaparib group compared to the placebo group:
    • HR, 0.68; 98.5% CI, 0.47-0.97; P = 0.009:
      • Four-year OS rates were 89.8% with olaparib and 86.4% with placebo
  • Continued benefit in terms of invasive disease free survival (IDFS) and distant DFS (DDFS) were demonstrated with olaparib versus placebo
  • In subset analyses, OS, IDFS, and DDFS benefits were observed across major subgroups

• At updated analysis, the safety findings were consistent with what had been reported previously:
  • Adverse events (AEs) associated with adjuvant abemaciclib are considered manageable and acceptable in this patient population
• The most common AEs reported (≥ 20%) in the abemaciclib plus endocrine therapy arm and at least 2% higher than in the endocrine therapy–alone arm were:
  • Diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache
  • The most frequently reported (≥ 5%) grade 3 or 4 AEs were:
    • Neutropenia, leukopenia, diarrhea, and lymphopenia
  • Clinicians should be aware of the potential for certain rare, but serious, toxicities:
    • Venous thromboembolism
    • Interstitial lung disease / pneumonitis

• Based on initial results from the monarchE trial:
  • The FDA approved abemaciclib plus endocrine therapy (tamoxifen or an aromatase inhibitor) for adjuvant treatment of:
    • Hormone receptor–positive
    • HER2-negative (HER2-)
    • Node-positive
    • Early breast cancer in patients at high risk of recurrence and with a Ki-67 score of 20% or higher (as determined by an FDA-approved test)
• This marked the first approval of a CDK4/6 inhibitor:
  • For use as adjuvant treatment of breast cancer
• The limitation of the indication to a Ki-67 score of at least 20% has generated some confusion and controversy in the field:
  • Especially in light of the subsequent guidance from the American Society of Clinical Oncology and the National Comprehensive Cancer Network:
    • Which both recommend patient selection for adjuvant abemaciclib plus endocrine therapy in accordance with the trial design

• For patients with early-stage breast cancer, gene expression assays can be used to determine the likelihood of recurrence and the potential benefit of adjuvant chemotherapy
• For example, the Oncotype Dx assay, which is based on the expression profile of 21 genes, provides a score (ie, recurrence score) that is both prognostic and predictive of chemotherapy benefit
• Node-negative tumors with a recurrence score of 0 to 10 have a very good prognosis, with a low rate of distant recurrence at 10 years
• Conversely, tumors with a high recurrence score (> 25) have higher risk for recurrence and have been shown to benefit from chemotherapy in retrospective studies
• In the TAILORx studies, postmenopausal patients with node-negative, HR+ early breast cancer and intermediate recurrence score (11 to 25) did not derive a significant benefit from chemotherapy, which is thus not recommended for this subgroup of patients

• The addition of abemaciclib to adjuvant endocrine therapy:
  • Was evaluated in the phase 3 monarchE trial:
    • That enrolled patients with high-risk, early-stage breast cancer:
      • With high risk defined as:
        • ≥ 4 axillary nodes or
        • 1 to 3 axillary nodes with:
          • Grade 3 histology
          • A large primary tumor (equal or greater than 5 cm)
          • High Ki67 score:
            • Defined as ≥ 20%
    • At a median 27 months of follow up:
      • The addition of abemaciclib led to statistically significant improvements in:
        • Invasive disease-free survival (IDFS) (HR, 0.70; 95% CI, 0.59-0.82; nominal P < 0.0001)
        • Distant relapse-free survival (DRFS) (HR, 0.69; 95% CI, 0.57-0.83; nominal P < 0.0001)
      • These findings were consistent with those from earlier data analyses
      • A low Ki-67 level was prognostic of better outcome:
        • However, it was not predictive of benefit from abemaciclib in this study
    • Results from a prespecified overall survival (OS) interim analysis were presented at the 2022 San Antonio Breast Cancer Symposium:
      • All patients were no longer receiving abemaciclib at a median follow-up of 42 months
      • Invasive DFS and DRFS benefits were sustained beyond the treatment period
      • OS data remained immature at time of analysis (Table 1.1)

Table 1.1. Efficacy Results From the monarchE Study Presented at SABCS 2022

• Most women don’t have any symptoms at diagnosis of breast cancer, which typically follows abnormalities at breast imaging detected through screening programs
• However, approximately 1 in 6 women with breast cancer present with symptoms other than a breast lump
• Of note, women with non-lump breast symptoms often delay seeking help, which is concerning as longer intervals to diagnosis have been associated with lower survival rates
• In the United States, approximately 6% of tumors are metastatic at presentation, which not rarely are diagnosed in patients with neglected tumors